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Sample records for factor-i receptor igf-ir

  1. The insulin-like growth factor-I receptor (IGF-IR) in breast cancer: biology and treatment strategies.

    Science.gov (United States)

    Motallebnezhad, Morteza; Aghebati-Maleki, Leili; Jadidi-Niaragh, Farhad; Nickho, Hamid; Samadi-Kafil, Hosein; Shamsasenjan, Karim; Yousefi, Mehdi

    2016-09-01

    Breast cancer is the most common cancer and the second leading cause of cancer-related deaths among women worldwide. Although patients are often diagnosed in the early and curable stages, the treatment of metastatic breast cancer remains a major clinical challenge. The combination of chemotherapy with new targeting agents, such as bevacizumab, is helpful in improving patient survival; however, novel treatment strategies are required to improve clinical outcomes. The insulin-like growth factor-I receptor (IGF-IR) is a tyrosine kinase cell surface receptor which is involved in the regulation of cell growth and metabolism. Previous studies have shown that activation of the IGF-IR signaling pathway promotes proliferation, survival, and metastasis of breast cancer cells. Additionally, overexpression of IGF-IR is associated with breast cancer cell resistance to anticancer therapies. Recently, IGF-IR has been introduced as a marker of stemness in breast cancer cells and there is also accumulating evidence that IGF-IR contributes to the establishment and maintenance of breast cancer epithelial-mesenchymal transition (EMT). Therefore, pharmacological or molecular targeting of IGF-IR could be a promising strategy, in the treatment of patients with breast cancer, particularly in order to circumvent the therapeutic resistance and targeting breast cancer stem/progenitors. Currently, many strategies have been developed for targeting IGF-IR, some have entered clinical trials and some are in preclinical stages for breast cancer therapy. In this review, we will first discuss on the biology of IGF-IR in an attempt to find the role of this receptor in breast cancer and then discuss about therapeutic strategies to target this receptor.

  2. The Role of Type I Insulin Like Growth Factor Receptor (IGF-IR) in Adult and Childhood Acute Lymphoblastic Leukemia

    International Nuclear Information System (INIS)

    KAMEL, M.M.; HAMMAM, A.A.; ELHOSEINY, Sh.M.; MOKHLES, A.; MOHSEN, E.

    2008-01-01

    Background: Type 1 insulin like growth factor receptor (IGF-IR) is over expressed in many tumors including hematological cancers. It is a critical signaling molecule for tumor cell proliferation and survival. Data suggest that IGF-IR antibodies can effectively and specifically inhibit cancer cell growth in vitro and in vivo. Blockage of IGF-IR expression could be a promising therapeutic approach for the management of cancer patients. Aim of Work: To characterize the expression pattern of IGF-IR gene in malignant lymphoblasts of children and adults suffering from ALL in relation to clinical features at diagnosis. Patients and Methods: The expression of IGF-IR was analyzed in 60 patients with ALL, 30 childhood ALL (16 newly diagnosed and 14 in complete remission) and 30 adulthood ALL (15 newly diagnosed and 15 in complete remission) together with 20 normal age and sex matched healthy controls using a Real-Time Quantitative Reverse- Transcriptase Polymerase Chain Reaction (RTQ-PCR) to assess the possible relation, association or correlation between IGF-IR expression and ALL clinical and laboratory features at diagnosis. Results: IGF-IR was expressed in all 60 patients with ALL; the expression levels of IGF-IR were significantly higher in newly diagnosed patients than in patients in complete remission (CR) and controls (p<0.001). There were no statistically significant differences in the expression of IGF-IR between patients with different clinical and laboratory features. Conclusion: IGF-1R seems to play a crucial role in patients with ALL since it is expressed in all ALL cases (adulthood and childhood). Therefore, new therapeutic agents targeting IGF-1R may provide a better chance for those patients

  3. Prognostic value of insulin- like growth factor-I receptor expression in renal cell carcinoma

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    Sichani Mehrdad

    2010-01-01

    Full Text Available The Insulin-Like growth factor-I receptor (IGF-IR, a tyrosine-kinas receptor over expressed in many tumor cell lines and in some human tumors, plays a critical role in trans-formation, tumorigenicity and metastasis. The aim of the present study is to investigate the role of IGF-IR expression as a prognostic factor in RCC. This study was conducted in a historical cohort of 82 patients who had RCC treated with radical nephrectomy from 1994 to 2005. Specimens were reevaluated with regard to histological subtype, nuclear grade, stage and IGF-IR expression. The IGF-IR stain was semi- quantitatively evaluated using the Allred score system. Kaplan-Meier analysis demonstrated a significant positive correlation between Fuhrman nuclear grade and IGF-IR Allred score (P< 0.0001. Survival in patients with score IGF-I ≤ 4 was 90.21 month and in patients with score IGF-1R> 4 was 33.39 month (P Value < 0.0001. Cox regression analysis in-dicated that expression of IGF-IR is a prognostic factor in patients with RCC (P Value < 0.0001, odds Ratio = 2.38. In conclusion, a statistically significant correlation was demonstrated between IGF-IR expression and Fuhrman nuclear grading and survival in patients with RCC. In stage-by-stage and grade-by-grade analysis; however, it seems that we cannot consider IGF-IR as an inde-pendent prognostic factor.

  4. Prognostic value of insulin- like growth factor-I receptor expression in renal cell carcinoma.

    Science.gov (United States)

    Sichani, Mehrdad Mohammadi; Yazdi, Fateme Sarreshtedar; Moghaddam, Noushin Afshar; Chehrei, Ali; Kabiri, Mahmud; Naeimi, Amin; Taheri, Diana

    2010-01-01

    The insulin-like growth factor-I receptor (IGF-IR), a tyrosine kinase receptor over expressed in many tumor cell lines and in some human tumors, plays a critical role in transformation, tumorigenicity and metastasis. The aim of the present study is to investigate the role of IGF-IR expression as a prognostic factor in RCC. This study was conducted in a historical cohort of 82 patients who had RCC treated with radical nephrectomy from 1994 to 2005. Specimens were reevaluated with regard to histological subtype, nuclear grade, stage and IGF-IR expression. The IGF-IR stain was semi-quantitatively evaluated using the Allred score system. Kaplan-Meier analysis demonstrated a significant positive correlation between Fuhrman nuclear grade and IGF-IR Allred score (P 4 was 33.39 month (P Value < 0.0001). Cox regression analysis indicated that expression of IGF-IR is a prognostic factor in patients with RCC (P Value < 0.0001, odds Ratio = 2.38). In conclusion, a statistically significant correlation was demonstrated between IGF-IR expression and Fuhrman nuclear grading and survival in patients with RCC. In stage-by-stage and grade-by-grade analysis; however, it seems that we cannot consider IGF-IR as an independent prognostic factor.

  5. Cell surface GRP78 facilitates hepatoma cells proliferation and migration by activating IGF-IR.

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    Yin, Yancun; Chen, Chen; Chen, Jinliang; Zhan, Renhui; Zhang, Qiang; Xu, Xiaoyan; Li, Defang; Li, Minjing

    2017-07-01

    The 78kDa glucose regulated protein (GRP78) is a multifunctional chaperone that is involved in a variety of cellular processes. Insulin like growth factor I receptor (IGF-IR) often aberrant expresses in many types of tumor cells. The IGF-IR signaling plays key roles in carcinogenesis and maintenance of the malignant phenotype. The crosstalk between GRP78 and IGF-IR molecules has not well been illuminated. Here, we demonstrated a reciprocal regulation of GRP78 expression and IGF-IR pathway activation. IGF-I induced GRP78 expression in hepatoma cells. IGF-IR knockdown or IGF-IR inhibitor repressed GRP78 expression. Both phosphatidylinositol 3-kianase (PI3K) and mitogen-activated protein kinase (MAPK) pathways involved in IGF-I induction of GRP78 expression. Interestingly, treatment of hepatoma cells with IGF-I re-distributes GRP78 from endoplasmic reticulum (ER) to cell surface and promotes its physical interaction with IGF-IR. Also, GRP78 promotes IGF-IR phosphorylation and activation. Blocked of GRP78 by small interfering RNA or inhibition of GRP78 function by (-)-epigallocatechin gallate (EGCG) blocks IGF-I induced IGF-IR phosphorylation and its downstream signaling. Further, blocked cell surface GRP78 with antibody inhibits IGF-I stimulated cellular proliferation and migration. These data reveal an essential role for the molecular chaperone GRP78 in IGF-IR signaling and implicate the use of GRP78 inhibitors in blocking IGF-IR signaling in hepatoma cells. Copyright © 2017 Elsevier Inc. All rights reserved.

  6. Increased hepatic expression of insulin-like growth factor-I receptor in chronic hepatitis C

    Science.gov (United States)

    Stefano, José Tadeu; Corrêa-Giannella, Maria Lúcia; Ribeiro, Cristiane Maria Freitas; Alves, Venâncio Avancini Ferreira; Massarollo, Paulo Celso Bosco; Machado, Marcel Cerqueira Cesar; Giannella-Neto, Daniel

    2006-01-01

    AIM: Although increased insulin-like growth factor-I receptor (IGF-IR) gene expression has been reported in hepatocellular carcinoma, studies assessing IGF-IR in chronic hepatitis C (CHC) and cirrhosis are scarce. We therefore aimed to evaluate IGF-IR and IGF-I mRNA expression in liver from patient with CHC. METHODS: IGF-IR and IGF-I mRNA content were determined by semi-quantitative RT-PCR and IGF-IR protein expression was determined by immunohisto-chemistry in hepatic tissue obtained from patients with CHC before (34 patients) and after (10 patients) therapy with interferon-α and ribavirin. RESULTS: An increase of IGF-IR mRNA content was observed in hepatic tissue obtained from all CHC patients as well as from 6 cadaveric liver donors following orthopic transplantation (an attempt to evaluate normal livers) in comparison to normal liver, while no relevant modifications were detected in IGF-I mRNA content. The immunohistochemical results showed that the raise in IGF-IR mRNA content was related both to ductular reaction and to increased IGF-IR expression in hepatocytes. A decrease in IGF-IR mRNA content was observed in patients who achieved sustained virological response after therapy, suggesting an improvement in hepatic damage. CONCLUSION: The up-regulation of IGF-IR expression in hepatocytes of patients with CHC could constitute an attempt to stimulate hepatocyte regeneration. Considering that liver is the organ with the highest levels of IGF-I, our finding of increased IGF-IR expression after both acute and chronic hepatic damage highlights the need for additional studies to elucidate the role of IGF-I in liver regeneration. PMID:16804965

  7. IGF-IR targeted therapy: Past, present and future

    NARCIS (Netherlands)

    J.A.M.J.L. Janssen (Joseph); A.J. Varewijck (Aimee)

    2014-01-01

    textabstractThe IGF-I receptor (IGF-IR) has been studied as an anti-cancer target. However, monotherapy trials with IGF-IR targeted antibodies or with IGF-IR specific tyrosine kinase inhibitors have, overall, been very disappointing in the clinical setting. This review discusses potential reasons

  8. Small interfering RNA targeted to IGF-IR delays tumor growth and induces proinflammatory cytokines in a mouse breast cancer model.

    Directory of Open Access Journals (Sweden)

    Tiphanie Durfort

    Full Text Available Insulin-like growth factor I (IGF-I and its type I receptor (IGF-IR play significant roles in tumorigenesis and in immune response. Here, we wanted to know whether an RNA interference approach targeted to IGF-IR could be used for specific antitumor immunostimulation in a breast cancer model. For that, we evaluated short interfering RNA (siRNAs for inhibition of in vivo tumor growth and immunological stimulation in immunocompetent mice. We designed 2'-O-methyl-modified siRNAs to inhibit expression of IGF-IR in two murine breast cancer cell lines (EMT6, C4HD. Cell transfection of IGF-IR siRNAs decreased proliferation, diminished phosphorylation of downstream signaling pathway proteins, AKT and ERK, and caused a G0/G1 cell cycle block. The IGF-IR silencing also induced secretion of two proinflammatory cytokines, TNF- α and IFN-γ. When we transfected C4HD cells with siRNAs targeting IGF-IR, mammary tumor growth was strongly delayed in syngenic mice. Histology of developing tumors in mice grafted with IGF-IR siRNA treated C4HD cells revealed a low mitotic index, and infiltration of lymphocytes and polymorphonuclear neutrophils, suggesting activation of an antitumor immune response. When we used C4HD cells treated with siRNA as an immunogen, we observed an increase in delayed-type hypersensitivity and the presence of cytotoxic splenocytes against wild-type C4HD cells, indicative of evolving immune response. Our findings show that silencing IGF-IR using synthetic siRNA bearing 2'-O-methyl nucleotides may offer a new clinical approach for treatment of mammary tumors expressing IGF-IR. Interestingly, our work also suggests that crosstalk between IGF-I axis and antitumor immune response can mobilize proinflammatory cytokines.

  9. Therapy of Prostate Cancer Using a Human Antibody Targeting the Type 1 Insulin-Like Growth Factor Receptor (IGF-IR)

    Science.gov (United States)

    2009-09-01

    delayed Majeed et al., 2005). All these studies suggest an essential role of IGF-IR in cellular transformation. Hongo et al. [1998] have identified...62:2942–2950. Hongo A, Yumet G, Resnicoff M, Romano G, O’Connor R, Baserga R. 1998. Inhibition of tumorigenesis and induc- tion of apoptosis in human...essential role of IGF-IR in cellular transformation. Hongo et al. [1998] have identified specific tyrosine residues on the b-subunit of the IGF-IR that

  10. Crosstalk between adiponectin and IGF-IR in breast cancer

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    Loredana eMauro

    2015-07-01

    Full Text Available Obesity is a chronic and multifactorial disorder that is reaching epidemic proportions. It is characterized by an enlarged mass of adipose tissue caused by a combination of size increase of preexisting adipocytes (hypertrophy and de novo adipocyte differentiation (hyperplasia. Obesity is related to many metabolic disorders like hypertension, type 2 diabetes, metabolic syndrome, cardiovascular disease, and it is associated with an increased risk of cancer development in different tissues including breast. Adipose tissue is now regarded as not just a storage reservoir for excess energy, but rather as an endocrine organ, secreting a large number of bioactive molecules called adipokines. Among these, adiponectin represents the most abundant adipose tissue-excreted protein, which exhibits insulin-sensitizing, anti-inflammatory and antiatherogenic properties. The serum concentrations of adiponectin are inversely correlated with body mass index. Recently, low levels of plasma adiponectin have been associated with an increased risk for obesity-related cancers and development of more aggressive phenotype, concomitantly with alterations in the bioavailability of Insulin-like Growth Factor-I (IGF-I and IGF-I Receptor (IGF-IR signaling pathways. In this review we discuss the cross-talk between adiponectin/AdipoR1 and IGF-I/IGF-IR in breast cancer.

  11. The phosphatidylinositol-3 kinase pathway is not essential for insulin-like growth factor I receptor-mediated clonogenic radioresistance

    International Nuclear Information System (INIS)

    Yu, Dong; Watanabe, Hiroshi; Shibuya, Hitoshi; Miura, Masahiko

    2002-01-01

    The insulin-like growth factor I receptor (IGF-IR) is known to induce clonogenic radioresistance in cells following ionizing irradiation. To explore the downstream signaling pathways, we focused on the phosphatidylinositol-3 kinase (PI3-K) pathway, which is thought to be the primary cell survival signal originating from the receptor. For this purpose, R- cells deficient in the endogenous IGF-IR were used as a recipient of the human IGF-IR with or without mutations at potential PI3-K activation sites: NPXY 950 and Y 1316 XXM. Mutats with double mutation at Y950/Y1316 exhibited not abrogated, but reduced activation of insulin receptor substance-1 (IRS-1), PI3-K, and Akt upon IGF-I stimulation. However, the mutants had the same clonogenic radioresistance as cells with wild type (WT) receptors. Neither wortmannin nor LY294002, specific inhibitors of PI3-K, affected the radioresistance of cells with WT receptors at concentrations specific for PI3-K. Collectively, these results indicate that the PI3-K pathway is not essential for IGF-IR-mediated clonogenic radioresistance. (author)

  12. Antiproliferative and apoptotic effects of a specific anti-insulin-like growth factor I receptor single chain antibody on breast cancer cells.

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    Motallebnezhad, Morteza; Younesi, Vahid; Aghebati-Maleki, Leili; Nickho, Hamid; Safarzadeh, Elham; Ahmadi, Majid; Movassaghpour, Ali Akbar; Hosseini, Ahmad; Yousefi, Mehdi

    2016-11-01

    Insulin-like growth factor I receptor (IGF-IR) is expressed on breast cancer cells and involves in metastasis, survival, and proliferation. Currently, application of IGF-IR-targeting monoclonal antibodies (mAbs), alone or in combination with other drugs, is a promising strategy for breast cancer therapy. Single-chain fragment variable (scFv) antibodies have been introduced as appropriate tools for tumor-targeting purposes because of their advantages over whole antibodies. In the present study, we employed a naïve phage library and isolated scFvs against a specific epitope from extracellular domain of IGF-IR by panning process. The selected scFvs were further characterized using polyclonal and monoclonal phage ELISA, soluble monoclonal ELISA, and colony PCR and sequencing. Antiproliferative and apoptotic effects of selected scFv antibodies on breast cancer cell lines were also evaluated by MTT and Annexin V/PI assays. The results of ELISA indicated specific reactions of the isolated scFvs against the IGF-IR peptide, and analyses of PCR product and sequencing confirmed the presence of full length V H and Vκ inserts. Treatment of MCF7 and SKBR3 cells with anti-IGF-IR scFv led to a significant growth inhibition. The results also showed that scFv treatment significantly augmented trastuzumab growth inhibitory effects on SKBR3 cells. The percentage of the apoptotic MCF7 and SKBR3 cells after 24-h treatment with scFv was 39 and 30.70 %, respectively. Twenty-four-hour treatment with scFv in combination with trastuzumab resulted in 44.75 % apoptosis of SKBR3 cells. Taken together, our results demonstrate that the targeting of IGF-IR by scFv can be an effective strategy in the treatment of breast cancer and provide further evidence for effectiveness of dual targeting of HER2 and IGF-IR in breast cancer therapy.

  13. New advances in understanding thyroid-associated ophthalmopathy and the potential role for insulin-like growth factor-I receptor [version 1; referees: 2 approved

    OpenAIRE

    Terry J Smith

    2018-01-01

    Thyroid-associated ophthalmopathy (TAO), a localized periocular manifestation of the autoimmune syndrome known as Graves’ disease, remains incompletely understood. Discussions of its pathogenesis are generally focused on the thyrotropin receptor, the proposed role for which is supported by substantial evidence. Considerations of any involvement of the insulin-like growth factor-I receptor (IGF-IR) in the disease are frequently contentious. In this brief, topically focused review, I have attem...

  14. IGF-IR promotes prostate cancer growth by stabilizing α5β1 integrin protein levels.

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    Aejaz Sayeed

    Full Text Available Dynamic crosstalk between growth factor receptors, cell adhesion molecules and extracellular matrix is essential for cancer cell migration and invasion. Integrins are transmembrane receptors that bind extracellular matrix proteins and enable cell adhesion and cytoskeletal organization. They also mediate signal transduction to regulate cell proliferation and survival. The type 1 insulin-like growth factor receptor (IGF-IR mediates tumor cell growth, adhesion and inhibition of apoptosis in several types of cancer. We have previously demonstrated that β1 integrins regulate anchorage-independent growth of prostate cancer (PrCa cells by regulating IGF-IR expression and androgen receptor-mediated transcriptional functions. Furthermore, we have recently reported that IGF-IR regulates the expression of β1 integrins in PrCa cells. We have dissected the mechanism through which IGF-IR regulates β1 integrin expression in PrCa. Here we report that IGF-IR is crucial for PrCa cell growth and that β1 integrins contribute to the regulation of proliferation by IGF-IR. We demonstrate that β1 integrin regulation by IGF-IR does not occur at the mRNA level. Exogenous expression of a CD4 - β1 integrin cytoplasmic domain chimera does not interfere with such regulation and fails to stabilize β1 integrin expression in the absence of IGF-IR. This appears to be due to the lack of interaction between the β1 cytoplasmic domain and IGF-IR. We demonstrate that IGF-IR stabilizes the β1 subunit by protecting it from proteasomal degradation. The α5 subunit, one of the binding partners of β1, is also downregulated along with β1 upon IGF-IR knockdown while no change is observed in the expression of the α2, α3, α4, α6 and α7 subunits. Our results reveal a crucial mechanistic role for the α5β1 integrin, downstream of IGF-IR, in regulating cancer growth.

  15. Decreased insulin-like growth factor-I and its receptor expression in the hippocampus and somatosensory cortex of the aged mouse.

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    Lee, Choong Hyun; Ahn, Ji Hyeon; Park, Joon Ha; Yan, Bing Chun; Kim, In Hye; Lee, Dae Hwan; Cho, Jeong-Hwi; Chen, Bai Hui; Lee, Jae-Chul; Cho, Jun Hwi; Lee, Yun Lyul; Won, Moo-Ho; Kang, Il-Jun

    2014-04-01

    Insulin-like growth factor-I (IGF-I) is a multifunctional polypeptide and has diverse effects on brain functions. In the present study, we compared IGF-I and IGF-I receptor (IGF-IR) immunoreactivity and their protein levels between the adult (postnatal month 6) and aged (postnatal month 24) mouse hippocampus and somatosensory cortex. In the adult hippocampus, IGF-I immunoreactivity was easily observed in the pyramidal cells of the stratum pyramidale in the hippocampus proper and in the granule cells of the granule cell layer of the dentate gyrus. In the adult somatosensory cortex, IGF-I immunoreactivity was easily found in the pyramidal cells of layer V. In the aged groups, IGF-I expression was dramatically decreased in the cells. Like the change of IGF-I immunoreactivity, IGF-IR immunoreactivity in the pyramidal and granule cells of the hippocampus and in the pyramidal cells of the somatosensory cortex was also markedly decreased in the aged group. In addition, both IGF-I and IGF-IR protein levels were significantly decreased in the aged hippocampus and somatosensory cortex. These results indicate that the apparent decrease of IGF-I and IGF-IR expression in the aged mouse hippocampus and somatosensory cortex may be related to age-related changes in the aged brain.

  16. Influence of the toxicity of cryoprotective agents on the involvement of insulin-like growth factor-I receptor in surf clam (Spisula sachalinensis) larvae.

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    Choi, Youn Hee; Nam, Taek Jeong

    2014-01-01

    The signaling of insulin-like growth factor-I (IGF-I) is involved in the development, growth, reproduction and aging of vertebrates. However, few studies have investigated the involvement of IGF-I during states of extreme shock, such as those induced by potently toxic cryoprotective agents (CPAs) or low temperature conditions, in bivalves. We investigated the toxicity of CPAs and the potential relationship between larval viability and the IGF-I receptor (IGF-IR) after treatment with CPAs or freezing in surf clam (Spisula sachalinensis) larvae. The umbo larvae and different concentrations of CPAs (dimethyl sulfoxide, DMSO; ethylene glycol, EG) were used to investigate the toxicity of CPAs and the vitrification of surf clam larvae. The relationship between larval viability and the IGF-I receptor (IGF-IR) after treatment with CPAs or freezing was investigated using immunoblot analysis. An increase in concentration greater than 4M DMSO was fatal in larvae; however, 5M EG combined with a mixture of CPAs had no harmful effects. Moreover, live larvae immersed in a 5M EG solution remained intact and maintained their normal shape and organs. However, even though the larvae survived the CPA toxicity test, none of the vitrified larvae survived. After immersion into CPAs and vitrification, 97-kDa IGF-IR ß-subunits could be detected in all larvae; but tyrosine phosphorylation of the intracellular β-subunits was detected only in the control and live groups. IGF-IR was activated in the umbo larvae but not in dead surf clam larvae treated with CPA and frozen. Activation of IGF-IR has relevance to the umbo larval stage in live surf clams treated with CPAs.

  17. IGF-IR cooperates with ERα to inhibit breast cancer cell aggressiveness by regulating the expression and localisation of ECM molecules

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    Afratis, Nikolaos A.; Bouris, Panagiotis; Skandalis, Spyros S.; Multhaupt, Hinke A.; Couchman, John R.; Theocharis, Achilleas D.; Karamanos, Nikos K.

    2017-01-01

    IGF-IR is highly associated with the behaviour of breast cancer cells. In ERα-positive breast cancer, IGF-IR is present at high levels. In clinical practice, prolonged treatment with anti-estrogen agents results in resistance to the therapy with activation of alternative signaling pathways. Receptor Tyrosine Kinases, and especially IGF-IR, have crucial roles in these processes. Here, we report a nodal role of IGF-IR in the regulation of ERα-positive breast cancer cell aggressiveness and the regulation of expression levels of several extracellular matrix molecules. In particular, activation of IGF-IR, but not EGFR, in MCF-7 breast cancer cells results in the reduction of specific matrix metalloproteinases and their inhibitors. In contrast, IGF-IR inhibition leads to the depletion by endocytosis of syndecan-4. Global important changes in cell adhesion receptors, which include integrins and syndecan-4 triggered by IGF-IR inhibition, regulate adhesion and invasion. Cell function assays that were performed in MCF-7 cells as well as their ERα-suppressed counterparts indicate that ER status is a major determinant of IGF-IR regulatory role on cell adhesion and invasion. The strong inhibitory role of IGF-IR on breast cancer cells aggressiveness for which E2-ERα signaling pathway seems to be essential, highlights IGF-IR as a major molecular target for novel therapeutic strategies. PMID:28079144

  18. Inactivation of Rac1 reduces Trastuzumab resistance in PTEN deficient and insulin-like growth factor I receptor overexpressing human breast cancer SKBR3 cells.

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    Zhao, Yong; Wang, Zhishan; Jiang, Yiguo; Yang, Chengfeng

    2011-12-26

    Drug resistance remains to be a big challenge in applying anti-HER2 monoclonal antibody Trastuzumab for treating breast cancer with HER2 overexpression. Amplification of insulin-like growth factor I receptor (IGF-IR) and deletion of tumor suppressor phosphatase and tensin homolog (PTEN) are implicated in Trastuzumab resistance, however, the underlying mechanisms have not been clearly defined. Activation of Rac1, a member of Rho GTPase family, is capable of causing cytoskeleton reorganization, regulating gene expression and promoting cell proliferation. To investigate the mechanism of Trastuzumab resistance, PTEN knockdown and IGF-IR overexpressing stable cell lines were generated in HER2 overexpression human breast cancer SKBR3 cells. Rac1 was highly activated in PTEN deficient and IGF-IR overexpressing Trastuzumab-resistant cells in a HER2-independent manner. Inactivation of Rac1 by using a Rac1 inhibitor NSC23766 or siRNA knocking down the expression of Tiam1, a guanine nucleotide exchange factor for Rac, significantly reduced Trastuzumab resistance in SKBR3 cells. Inhibition of Rac1 had no effect on the levels of phosphor-HER2 and phosphor-Akt, but significantly decreased the levels of cyclin D1 in Trastuzumab-resistant cells. Inhibition of Akt with an Akt inhibitor also significantly reduced Trastuzumab resistance. However, simultaneous inhibition of both Rac1 and Akt resulted in a significantly more decrease of Trastuzumab resistance than inactivation of Rac1 or Akt alone. These results suggest that Rac1 activation is critically involved in Trastuzumab resistance caused by PTEN deletion or IGF-IR overexpression. Simultaneous inhibition of Rac1 and Akt may represent a promising strategy in reducing Trastuzumab resistance in HER2 overexpression breast cancer. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

  19. Prioritization of EGFR/IGF-IR/VEGFR2 combination targeted therapies utilizing cancer models.

    Science.gov (United States)

    Tonra, James R; Corcoran, Erik; Deevi, Dhanvanthri S; Steiner, Philipp; Kearney, Jessica; Li, Huiling; Ludwig, Dale L; Zhu, Zhenping; Witte, Larry; Surguladze, David; Hicklin, Daniel J

    2009-06-01

    Rational strategies utilizing anticancer efficacy and biological principles are needed for the prioritization of specific combination targeted therapy approaches for clinical development, from among the many with experimental support. Antibodies targeting epidermal growth factor receptor (EGFR) (cetuximab), insulin-like growth factor-1 receptor (IGF-IR) (IMC-A12) or vascular endothelial growth factor receptor 2 (VEGFR2) (DC101), were dosed alone or in combination, in 11 human tumor xenograft models established in mice. Efficacy readouts included the tumor burden and incidence of metastasis, as well as tumor active hypoxia inducible factor-1 (HIF-1), human VEGF and blood vessel density. Cetuximab and DC101 contributed potent and non-overlapping benefits to the combination approach. Moreover, DC101 prevented escape from IMC-A12 + cetuximab in a colorectal cancer model and cetuximab prevented escape from DC101 therapy in a pancreatic cancer model. Targeting VEGFR2 + EGFR was prioritized over other treatment strategies utilizing EGFR, IGF-IR and VEGFR2 antibodies. The criteria that proved to be valuable were a non-overlapping spectrum of anticancer activity and the prevention of resistance to another therapy in the combination.

  20. Overexpression of IGF-I receptor in HeLa cells enhances in vivo radioresponse

    International Nuclear Information System (INIS)

    Kaneko, Haruna; Yu, Dong; Miura, Masahiko

    2007-01-01

    Insulin-like growth factor I receptor (IGF-IR) is a transmembrane receptor tyrosine kinase whose activation strongly promotes cell growth and survival. We previously reported that IGF-IR activity confers intrinsic radioresistance in mouse embryo fibroblasts in vitro. However, it is still unclear whether tumor cells overexpressing IGF-IR exhibit radioresistance in vivo. For this purpose, we established HeLa cells that overexpress IGF-IR (HeLa-R), subcutaneously transplanted these cells into nude mice, and examined radioresponse in the resulting solid tumors. HeLa-R cells exhibited typical in vitro phenotypes generally observed in IGF-IR-overexpressing cells, as well as significant intrinsic radioresistance in vitro compared with parent cells. As expected, the transplanted HeLa-R tumors grew at a remarkably higher rate than parent tumors. Histological analysis revealed that HeLa-R tumors expressed more VEGF and had a higher density of tumor vessels. Unexpectedly, a marked growth delay was observed in HeLa-R tumors following 10 Gy of X-irradiation. Immunostaining of HeLa-R tumors for the hypoxia marker pimonidazole revealed a significantly lower level of hypoxic cells. Moreover, clamp hypoxia significantly increased radioresistance in HeLa-R tumors. Tumor microenvironments in vivo generated by the IGF-IR expression thus could be a major factor in determining the tumor radioresponse in vivo

  1. c-Src, Insulin-Like Growth Factor I Receptor, G-Protein-Coupled Receptor Kinases and Focal Adhesion Kinase are Enriched Into Prostate Cancer Cell Exosomes.

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    DeRita, Rachel M; Zerlanko, Brad; Singh, Amrita; Lu, Huimin; Iozzo, Renato V; Benovic, Jeffrey L; Languino, Lucia R

    2017-01-01

    It is well known that Src tyrosine kinase, insulin-like growth factor 1 receptor (IGF-IR), and focal adhesion kinase (FAK) play important roles in prostate cancer (PrCa) development and progression. Src, which signals through FAK in response to integrin activation, has been implicated in many aspects of tumor biology, such as cell proliferation, metastasis, and angiogenesis. Furthermore, Src signaling is known to crosstalk with IGF-IR, which also promotes angiogenesis. In this study, we demonstrate that c-Src, IGF-IR, and FAK are packaged into exosomes (Exo), c-Src in particular being highly enriched in Exo from the androgen receptor (AR)-positive cell line C4-2B and AR-negative cell lines PC3 and DU145. Furthermore, we show that the active phosphorylated form of Src (Src pY416 ) is co-expressed in Exo with phosphorylated FAK (FAK pY861 ), a known target site of Src, which enhances proliferation and migration. We further demonstrate for the first time exosomal enrichment of G-protein-coupled receptor kinase (GRK) 5 and GRK6, both of which regulate Src and IGF-IR signaling and have been implicated in cancer. Finally, Src pY416 and c-Src are both expressed in Exo isolated from the plasma of prostate tumor-bearing TRAMP mice, and those same mice have higher levels of exosomal c-Src than their wild-type counterparts. In summary, we provide new evidence that active signaling molecules relevant to PrCa are enriched in Exo, and this suggests that the Src signaling network may provide useful biomarkers detectable by liquid biopsy, and may contribute to PrCa progression via Exo. J. Cell. Biochem. 118: 66-73, 2017. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  2. β-Catenin/POU5F1/SOX2 transcription factor complex mediates IGF-I receptor signaling and predicts poor prognosis in lung adenocarcinoma.

    Science.gov (United States)

    Xu, Chuan; Xie, Dan; Yu, Shi-Cang; Yang, Xiao-Jun; He, Li-Ru; Yang, Jing; Ping, Yi-Fang; Wang, Bin; Yang, Lang; Xu, Sen-Lin; Cui, Wei; Wang, Qing-Liang; Fu, Wen-Juan; Liu, Qing; Qian, Cheng; Cui, You-Hong; Rich, Jeremy N; Kung, Hsiang-Fu; Zhang, Xia; Bian, Xiu-Wu

    2013-05-15

    Cancer stem-like cells (CSLC) are crucial in tumor initiation and progression; however, the underlying mechanism for the self-renewal of cancer cells remains undefined. In the study, immunohistochemical analysis of specimens freshly excised from patients with lung adenocarcinoma showed that high expression of insulin-like growth factor I receptor (IGF-IR) in lung adenocarcinoma cells was positively correlated with the expressions of cancer stem cell markers CD133 and aldehyde dehydrogenase 1 family member A1 (ALDH1A1). IGF-IR activation enhanced POU class 5 homeobox 1 (POU5F1) expression on human lung adenocarcinoma stem-like cells (LACSLC) through PI3K/AKT/GSK3β/β-catenin cascade. POU5F1 could form a novel complex with β-catenin and SOX2 to bind Nanog promoter for transcription to maintain self-renewal of LACSLCs, which was dependent on the functional IGF-IR. Genetic and pharmacologic inhibition of IGF-IR abrogated LACSLC capabilities for self-renewal and tumorigenicity in vitro. In an in vivo xenograft tumor model, knockdown of either IGF-IR or POU5F1 impeded tumorigenic potentials of LACSLCs. By analyzing pathologic specimens excised from 200 patients with lung adenocarcinoma, we found that colocalization of highly expressed IGF-IR with β-catenin and POU5F1 predicted poor prognosis. Taken together, we show that IGF-IR-mediated POU5F1 expression to form a complex with β-catenin and SOX2 is crucial for the self-renewal and oncogenic potentials of LACSLCs, and the integrative clinical detection of the expressions of IGF-IR, β-catenin, and POU5F1 is indicatory for predicting prognosis in the patients of lung adenocarcinoma. ©2013 AACR.

  3. Association between IGF-IR gene polymorphisms and productive and reproductive traits in Holstein cows Associação entre polimorfismos do gene IGF-IR e características produtivas e reprodutivas em fêmeas bovinas da raça Holandesa

    Directory of Open Access Journals (Sweden)

    W. Schoenau

    2005-12-01

    Full Text Available The association between single-strand conformation polymorphism (SSCP in the gene of insulin-like growth factor-I receptor (IGF-IR and age at first calving (AFC, calving interval (CI, lactation length (LL, and milk yield (MY was studied using 106 graded Holstein females. The polimerase chain reaction (PCR with specific initiating oligonucleotides, resulted an amplified fragment of 335pb. The population genotypes frequencies were 82.1% and 17.9%, for AA and AB genotypes, respectively. The frequency of A allele was 0.91 and 0.09 of B allele. No association between the identified polymorphism and AFC, CI, and MY was observed. The LL was positively associated (PEstudou-se a associação entre polimorfismos de conformação de fita simples (SSCP no gene do receptor do fator-I de crescimento semelhante à insulina (IGF-IR e idade ao primeiro parto (IPP, intervalo entre partos (IEP, duração da lactação (DL e produção de leite (PL, em 106 fêmeas puras por cruza da raça Holandesa. A reação em cadeia da polimerase (PCR com oligonucleotídeos iniciadores específicos gerou um fragmento de 335pb. A freqüência genotípica da população para o polimorfismo foi 82,1% de indivíduos homozigotos para o alelo A e 17,9% de heterozigotos (AB. A freqüência do alelo A foi 0,91 e a do alelo B, 0,09. Não foi encontrada associação entre o polimorfismo estudado e as características IPP, IEP e PL. A característica DL foi positivamente associada (P<0,05 à ausência do alelo B. A lactação dos animais portadores do genótipo AA foi mais longa.

  4. Circulating Insulin-Like Growth Factor I Regulates Its Receptor in the Brain of Male Mice.

    Science.gov (United States)

    Trueba-Saiz, A; Fernandez, A M; Nishijima, T; Mecha, M; Santi, A; Munive, V; Aleman, I Torres

    2017-02-01

    The role of IGF-1 and its receptor (IGF-1R) in brain pathology is still unclear. Thus, either reduction of IGF-IR or treatment with IGF-1, two apparently opposite actions, has proven beneficial in brain diseases such as Alzheimer's dementia. A possible explanation of this discrepancy is that IGF-1 down-regulates brain IGF-1R levels, as previously seen in a mouse Alzheimer's dementia model. We now explored whether under normal conditions IGF-1 modulates its receptor. We first observed that in vitro, IGF-1 reduced IGF-1R mRNA levels in all types of brain cells including neurons, astrocytes, microglia, endothelial cells, and oligodendrocytes. IGF-1 also inhibited its own expression in neurons and brain endothelium. Next, we analyzed the in vivo actions of IGF-1. Because serum IGF-1 can enter the brain, we injected mice with IGF-1 ip. As soon as 1 hour after the injection, decreased hippocampal IGF-1 levels were observed, followed by increased IGF-1 and IGF-1R mRNAs 6 hours later. Because environmental enrichment (EE) stimulates the entrance of serum IGF-1 into the brain, we analyzed whether a physiological entrance of IGF-1 also produced changes in brain IGF-1R. Stimulation of IGF-1R by EE triggered a gradual decrease in hippocampal IGF-1 levels. After 6 hours of EE exposure, IGF-1 levels reached a significant decrease in parallel with increased IGF-1R expression. After longer times, IGF-1R mRNA levels returned to baseline. Thus, under nonpathological conditions, IGF-1 regulates brain IGF-1R. Because baseline IGF-1R levels are rapidly restored, a tight control of brain IGF-1R expression seems to operate under physiological conditions. Copyright © 2017 by the Endocrine Society.

  5. Bcl-2 and N-Myc Coexpression Increases IGF-IR and Features of Malignant Growth in Neuroblastoma Cell Lines

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    Rama Jasty

    2001-01-01

    Full Text Available The bcl-2 and c-myc oncogenes cooperate to transform multiple cell types. In the pediatric malignancy NB2, Bcl2 is highly expressed. In tumors with a poor prognosis, N-Myc, a protein homologous to c-Myc, is overexpressed as a result of gene amplification. The present study was designed to determine whether Bcl-2 cooperates with N-Myc to bestow a tumorigenic phenotype to neuroblastoma (NB cells. NB cell lines that at baseline express neither Bcl-2 nor N-Myc were stably transfected to express these gene products. In this model, we found Bcl-2 rescues N-Myc-expressing cells from apoptosis induced by serum withdrawal. Coexpression of Bcl-2 and N-Myc supports growth in low serum conditions and anchorage-independent growth in soft agar. Similarly, in vivo tumorigenic and angiogenic activity was dependent on coexpression. Our data further suggests that the mechanism underlying these changes involves the receptor for insulin growth factor type I (IGF-IR.

  6. Changing the insulin receptor to possess insulin-like growth factor I ligand specificity

    International Nuclear Information System (INIS)

    Andersen, A.S.; Kjeldsen, T.; Wiberg, F.C.; Christensen, P.M.; Rasmussen, J.S.; Norris, K.; Moeller, K.B.; Moeller, N.P.H.

    1990-01-01

    To examine the role of the N-terminal part of the insulin-like growth factor I (IGF-I) receptor and insulin receptor in determining ligand specificity, the authors prepared an expression vector encoding a hybrid receptor where exon 1 (encoding the signal peptide and seven amino acids of the α-subunit), exon 2, and exon 3 of the insulin receptor were replaced with the corresponding IGF-I receptor cDNA (938 nucleotides). To allow direct quantitative comparison of the binding capabilities of this hybrid receptor with those of the human IGF-I receptor and the insulin receptor, all three receptors were expressed in baby hamster kidney (BHK) cells as soluble molecules and partially purified before characterization. The hybrid IGF-I/insulin receptor bound IGF-I with an affinity comparable to that of the wild-type IGF-I receptor. In contrast, the hybrid receptor no longer displayed high-affinity binding of insulin. These results directly demonstrate that it is possible to change the specificity of the insulin receptor to that of the IGF-I receptor and, furthermore, that the binding specificity for IGF-I is encoded within the nucleotide sequence from 135 to 938 of the IGF-I receptor cDNA. Since the hybrid receptor only bound insulin with low affinity, the insulin binding region is likely to be located within exons 2 and 3 of the insulin receptor

  7. Changing the insulin receptor to possess insulin-like growth factor I ligand specificity

    Energy Technology Data Exchange (ETDEWEB)

    Andersen, A.S.; Kjeldsen, T.; Wiberg, F.C.; Christensen, P.M.; Rasmussen, J.S.; Norris, K.; Moeller, K.B.; Moeller, N.P.H. (Biopharmaceuticals Div., Bagsvaerd (Denmark))

    1990-08-14

    To examine the role of the N-terminal part of the insulin-like growth factor I (IGF-I) receptor and insulin receptor in determining ligand specificity, the authors prepared an expression vector encoding a hybrid receptor where exon 1 (encoding the signal peptide and seven amino acids of the {alpha}-subunit), exon 2, and exon 3 of the insulin receptor were replaced with the corresponding IGF-I receptor cDNA (938 nucleotides). To allow direct quantitative comparison of the binding capabilities of this hybrid receptor with those of the human IGF-I receptor and the insulin receptor, all three receptors were expressed in baby hamster kidney (BHK) cells as soluble molecules and partially purified before characterization. The hybrid IGF-I/insulin receptor bound IGF-I with an affinity comparable to that of the wild-type IGF-I receptor. In contrast, the hybrid receptor no longer displayed high-affinity binding of insulin. These results directly demonstrate that it is possible to change the specificity of the insulin receptor to that of the IGF-I receptor and, furthermore, that the binding specificity for IGF-I is encoded within the nucleotide sequence from 135 to 938 of the IGF-I receptor cDNA. Since the hybrid receptor only bound insulin with low affinity, the insulin binding region is likely to be located within exons 2 and 3 of the insulin receptor.

  8. FUS-DDIT3 Fusion Protein-Driven IGF-IR Signaling is a Therapeutic Target in Myxoid Liposarcoma.

    Science.gov (United States)

    Trautmann, Marcel; Menzel, Jasmin; Bertling, Christian; Cyra, Magdalene; Isfort, Ilka; Steinestel, Konrad; Elges, Sandra; Grünewald, Inga; Altvater, Bianca; Rossig, Claudia; Fröhling, Stefan; Hafner, Susanne; Simmet, Thomas; Åman, Pierre; Wardelmann, Eva; Huss, Sebastian; Hartmann, Wolfgang

    2017-10-15

    Purpose: Myxoid liposarcoma is an aggressive disease with particular propensity to develop hematogenic metastases. Over 90% of myxoid liposarcoma are characterized by a reciprocal t(12;16)(q13;p11) translocation. The resulting chimeric FUS-DDIT3 fusion protein plays a crucial role in myxoid liposarcoma pathogenesis; however, its specific impact on oncogenic signaling pathways remains to be substantiated. We here investigate the functional role of FUS-DDIT3 in IGF-IR/PI3K/Akt signaling driving myxoid liposarcoma pathogenesis. Experimental Design: Immunohistochemical evaluation of key effectors of the IGF-IR/PI3K/Akt signaling axis was performed in a comprehensive cohort of myxoid liposarcoma specimens. FUS-DDIT3 dependency and biological function of the IGF-IR/PI3K/Akt signaling cascade were analyzed using a HT1080 fibrosarcoma-based myxoid liposarcoma tumor model and multiple tumor-derived myxoid liposarcoma cell lines. An established myxoid liposarcoma avian chorioallantoic membrane model was used for in vivo confirmation of the preclinical in vitro results. Results: A comprehensive subset of myxoid liposarcoma specimens showed elevated expression and phosphorylation levels of various IGF-IR/PI3K/Akt signaling effectors. In HT1080 fibrosarcoma cells, overexpression of FUS-DDIT3 induced aberrant IGF-IR/PI3K/Akt pathway activity, which was dependent on transcriptional induction of the IGF2 gene. Conversely, RNAi-mediated FUS-DDIT3 knockdown in myxoid liposarcoma cells led to an inactivation of IGF-IR/PI3K/Akt signaling associated with diminished IGF2 mRNA expression. Treatment of myxoid liposarcoma cell lines with several IGF-IR inhibitors resulted in significant growth inhibition in vitro and in vivo Conclusions: Our preclinical study substantiates the fundamental role of the IGF-IR/PI3K/Akt signaling pathway in myxoid liposarcoma pathogenesis and provides a mechanism-based rationale for molecular- targeted approaches in myxoid liposarcoma cancer therapy. Clin

  9. IGF-IR cooperates with ERα to inhibit breast cancer cell aggressiveness by regulating the expression and localisation of ECM molecules

    DEFF Research Database (Denmark)

    Afratis, Nikolaos A; Bouris, Panagiotis; Skandalis, Spyros S

    2017-01-01

    and syndecan-4 triggered by IGF-IR inhibition, regulate adhesion and invasion. Cell function assays that were performed in MCF-7 cells as well as their ERα-suppressed counterparts indicate that ER status is a major determinant of IGF-IR regulatory role on cell adhesion and invasion. The strong inhibitory role...

  10. Autoinhibition of the insulin-like growth factor I receptor by the juxtamembrane region.

    Science.gov (United States)

    Craddock, Barbara P; Cotter, Christopher; Miller, W Todd

    2007-07-10

    The juxtamembrane (JM) regions of several receptor tyrosine kinases are involved in autoinhibitory interactions that maintain the low basal activity of the receptors; mutations can give rise to constitutive kinase activity and signaling. In this report, we show that the JM region of the human insulin-like growth factor I receptor (IGF1R) plays a role in kinase regulation. We mutated JM residues that were conserved in this subfamily of receptor tyrosine kinases, and expressed and purified the cytoplasmic domains using the Sf9/baculovirus system. We show that a kinase-proximal mutation (Y957F) and (to a lesser extent) a mutation in the central part of the JM region (N947A) increase the autophosphorylation activity of the kinase. Steady-state kinetic measurements show the mutations cause an increase in V(max) for phosphorylation of peptide substrates. When the holoreceptors were expressed in fibroblasts derived from IGF1R-deficient mice, the Y957F mutation led to a large increase in basal and in IGF1-stimulated receptor autophosphorylation. Together, these data demonstrate that the JM region of IGF1R plays an important role in limiting the basal activity of the receptor.

  11. Induction of apoptosis by a peptide from Porphyra yezoensis: regulation of the insulin-like growth factor I receptor signaling pathway in MCF-7 cells.

    Science.gov (United States)

    Park, Su-Jin; Ryu, Jina; Kim, In-Hye; Choi, Youn-Hee; Nam, Taek-Jeong

    2014-09-01

    This study examined how PPY, a peptide from Porphyra yezoensis, regulates multiple cell growth-related signaling pathways in MCF-7 cells. This study determined that PPY induces cell cycle arrest and inhibits the IGF-IR signaling pathway. Cell proliferation studies revealed that PPY induced cell death in a dose-dependent manner. Expression levels of IGF-IR were decreased in MCF-7 cells by PPY in a dose‑dependent manner. These results indicate that inhibition of the IGF-IR pathway is also involved in PPY induced proliferation of MCF-7 cells. In addition, these data demonstrated that PPY induces cell cycle arrest and activates apoptosis.

  12. Effect of whole-body vibration and insulin-like growth factor-I on muscle paralysis-induced bone degeneration after botulinum toxin injection in mice.

    Science.gov (United States)

    Niehoff, Anja; Lechner, Philipp; Ratiu, Oana; Reuter, Sven; Hamann, Nina; Brüggemann, Gert-Peter; Schönau, Eckhard; Bloch, Wilhelm; Beccard, Ralf

    2014-04-01

    Botulinum toxin A (BTX)-induced muscle paralysis results in pronounced bone degradation with substantial bone loss. We hypothesized that whole-body vibration (WBV) and insulin-like growth factor-I (IGF-I) treatment can counteract paralysis-induced bone degradation following BTX injections by activation of the protein kinase B (Akt) signaling pathway. Female C57BL/6 mice (n = 60, 16 weeks) were assigned into six groups (n = 10 each): SHAM, BTX, BTX+WBV, BTX+IGF-I, BTX+WBV+IGF-I, and a baseline group, which was killed at the beginning of the study. Mice received a BTX (1.0 U/0.1 mL) or saline (SHAM) injection in the right hind limb. The BTX+IGF-I and BTX+WBV+IGF-I groups obtained daily subcutaneous injections of human IGF-I (1 μg/day). The BTX+WBV and BTX+WBV+IGF-I groups underwent WBV (25 Hz, 2.1 g, 0.83 mm) for 30 min/day, 5 days/week for 4 weeks. Femora were scanned by pQCT, and mechanical properties were determined. On tibial sections TRAP staining, static histomorphometry, and immunohistochemical staining against Akt, phospho-Akt, IGF-IR (IGF-I receptor), and phospho-IGF-IR were conducted. BTX injection decreased trabecular and cortical bone mineral density. The WBV and WBV+IGF-I groups showed no difference in trabecular bone mineral density compared to the SHAM group. The phospho-IGF-IR and phospho-Akt stainings were not differentially altered in the injected hind limbs between groups. We found that high-frequency, low-magnitude WBV can counteract paralysis-induced bone loss following BTX injections, while we could not detect any effect of treatment with IGF-I.

  13. Multiple phosphorylation events control chicken ovalbumin upstream promoter transcription factor I orphan nuclear receptor activity.

    Science.gov (United States)

    Gay, Frédérique; Baráth, Peter; Desbois-Le Péron, Christine; Métivier, Raphaël; Le Guével, Rémy; Birse, Darcy; Salbert, Gilles

    2002-06-01

    Chicken ovalbumin upstream promoter transcription factor I (COUP-TFI) is an orphan member of the nuclear hormone receptor superfamily that comprises key regulators of many biological functions, such as embryonic development, metabolism, homeostasis, and reproduction. Although COUP-TFI can both actively silence gene transcription and antagonize the functions of various other nuclear receptors, the COUP-TFI orphan receptor also acts as a transcriptional activator in certain contexts. Moreover, COUP-TFI has recently been shown to serve as an accessory factor for some ligand-bound nuclear receptors, suggesting that it may modulate, both negatively and positively, a wide range of hormonal responses. In the absence of any identified cognate ligand, the mechanisms involved in the regulation of COUP-TFI activity remain unclear. The elucidation of several putative phosphorylation sites for MAPKs, PKC, and casein kinase II within the sequence of this orphan receptor led us to investigate phosphorylation events regulating the various COUP-TFI functions. After showing that COUP-TFI is phosphorylated in vivo, we provide evidence that in vivo inhibition of either MAPK or PKC signaling pathway leads to a specific and pronounced decrease in COUP-TFI-dependent transcriptional activation of the vitronectin gene promoter. Focusing on the molecular mechanisms underlying the MAPK- and PKC-mediated regulation of COUP-TFI activity, we show that COUP-TFI can be directly targeted by PKC and MAPK. These phosphorylation events differentially modulate COUP-TFI functions: PKC-mediated phosphorylation enhances COUP-TFI affinity for DNA and MAPK-mediated phosphorylation positively regulates the transactivation function of COUP-TFI, possibly through enhancing specific coactivator recruitment. These data provide evidence that COUP-TFI is likely to integrate distinct signaling pathways and raise the possibility that multiple extracellular signals influence biological processes controlled by COUP-TFI.

  14. Interaction of the αβ dimers of the insulin-like growth factor I receptor required for receptor autophosphorylation

    International Nuclear Information System (INIS)

    Tollesfsen, S.E.; Stoszek, R.M.; Thompson, K.

    1991-01-01

    The authors have recently found that association of the two αβ dimers of the insulin-like growth factor I (IGF I) receptor is required for formation of a high-affinity binding site for IGF I. To determine the structural requirements for IGF I activated kinase activity, they have examined the effect of dissociation of the two αβ dimers of the IGF I receptor on β subunit autophosphorylation. The αβ dimers formed after treatment with 2 mM dithiothreitol (DTT) at pH 8.75 for 5 min were separated from IGF I receptor remaining as tetramers after DTT treatment by fast protein liquid chromatography on a Superose 6 gel filtration column. Purification of the αβ dimers was confirmed by Western blot analysis using 125 I-labeled αIR-3, a monoclonal antibody to the IGF I receptor. Autophosphorylation of the IGF I receptor (αβ) 2 tetramer, treated without DTT or remaining after DTT treatment, is stimulated 1.6-2.9-fold by IGF I. In contrast, autophosporylation of the αβ dimers incubated in the presence or absence of IGF I (100 ng/mL) does not occur. Both IGF I receptor dimers and tetramers exhibit similar kinase activities using the synthetic substrate Arg-Arg-Leu-Ile-Glu-Asp-Ala-Glu-Tyr-Ala-Ala-Arg-Gly, indicating that the failure to detect autophosphorylation of the IGF I receptor dimers does not result from inactivation of the kinase by DTT treatment. They conclude that autophosphorylation of the IGF I receptor depends upon the interaction of the two αβ dimers

  15. The ligand specificities of the insulin receptor and the insulin-like growth factor I receptor reside in different regions of a common binding site

    Energy Technology Data Exchange (ETDEWEB)

    Kjeldsen, T.; Andersen, A.S.; Wiberg, F.C.; Rasmussen, J.S.; Schaeffer, L.; Balschmidt, P.; Moller, K.B.; Moller, N.P.H. (Novo Nordisk, Bagsvaerd (Denmark))

    1991-05-15

    To identify the region(s) of the insulin receptor and the insulin-like growth factor I (IGF-I) receptor responsible for ligand specificity (high-affinity binding), expression vectors encoding soluble chimeric insulin/IGF-I receptors were prepared. The chimeric receptors were expressed in mammalian cells and partially purified. Binding studies revealed that a construct comprising an IGF-I receptor in which the 68 N-terminal amino acids of the insulin receptor {alpha}-subunit had replaced the equivalent IGF-I receptor segment displayed a markedly increased affinity for insulin. In contrast, the corresponding IGF-I receptor sequence is not critical for high-affinity IGF-I binding. It is shown that part of the cysteine-rich domain determines IGF-I specificity. The authors have previously shown that exchanging exons 1, 2, and 3 of the insulin receptor with the corresponding IGF-I receptor sequence results in loss of high affinity for insulin and gain of high affinity for IGF-I. Consequently, it is suggested that the ligand specificities of the two receptors (i.e., the sequences that discriminate between insulin and IGF-I) reside in different regions of a binding site with common features present in both receptors.

  16. Experimental diabetes increases insulin-like growth factor I and II receptor concentration and gene expression in kidney

    International Nuclear Information System (INIS)

    Werner, H.; Shen-Orr, Z.; Stannard, B.; Burguera, B.; Roberts, C.T. Jr.; LeRoith, D.

    1990-01-01

    Insulinlike growth factor I (IGF-I) is a mitogenic hormone with important regulatory roles in growth and development. One of the target organs for IGF-I action is the kidney, which synthesizes abundant IGF-I receptors and IGF-I itself. To study the involvement of IGF-I and the IGF-I receptor in the development of nephropathy, one of the major complications of diabetes mellitus, we measured the expression of these genes in the kidney and in other tissues of the streptozocin-induced diabetic rat. The binding of 125I-labeled IGF-I to crude membranes was measured in the same tissues. We observed a 2.5-fold increase in the steady-state level of IGF-I-receptor mRNA in the diabetic kidney, which was accompanied by a 2.3-fold increase in IGF-I binding. In addition to this increase in IGF-I binding to the IGF-I receptor, there was also binding to a lower-molecular-weight material that may represent an IGF-binding protein. No change was detected in the level of IGF-I-peptide mRNA. Similarly, IGF-II-receptor mRNA levels and IGF-II binding were significantly increased in the diabetic kidney. IGF-I- and IGF-II-receptor mRNA levels and IGF-I and IGF-II binding returned to control values after insulin treatment. Because the IGF-I receptor is able to transduce mitogenic signals on activation of its tyrosine kinase domain, we hypothesize that, among other factors, high levels of receptor in the diabetic kidney may also be involved in the development of diabetic nephropathy. Increased IGF-II-receptor expression in the diabetic kidney may be important for the intracellular transport and packaging of lysosomal enzymes, although a role for this receptor in signal transduction cannot be excluded. Finally, the possible role of IGF-binding proteins requires further study

  17. Type I Insulin-like Growth Factor Receptor Induces Pulmonary Tumorigenesis

    Directory of Open Access Journals (Sweden)

    Nicolle M. Linnerth

    2009-07-01

    Full Text Available Despite the type I insulin-like growth factor receptor (IGF-IR being highly expressed in more than 80% of human lung tumors, a transgenic model of IGF-IR overexpression in the lung has not been created. We produced two novel transgenic mouse models in which IGF-IR is overexpressed in either lung type II alveolar cells (surfactant protein C [SPC]-IGFIR or Clara cells (CCSP-IGFIR in a doxycycline-inducible manner. Overexpression of IGF-IR in either cell type caused multifocal adenomatous alveolar hyperplasia with papillary and solid adenomas. These tumors expressed thyroid transcription factor 1 and Kruppel-like factor 5 in most tumor cells. Similar to our previous work with lung tumors that developed in the mouse mammary tumor virus-IGF-II transgenic mice, the lung tumors that develop in the SPC-IGFIR and CCSP-IGFIR transgenic mice expressed high levels of the cyclic adenosine monophosphate response element binding protein that was localized primarily to the nucleus. Although elevated IGF-IR expression can initiate lung tumor development, tumors can become independent of IGF-IR signaling as IGF-IR down-regulation in established tumors produced tumor regression in some, but not all, of the tumors. These findings implicate IGF-IR as an important initiator of lung tumorigenesis and suggest that the SPC-IGFIR and CCSP-IGFIR transgenic mice can be used to further our understanding of human lung cancer and the role IGF-IR plays in this disease.

  18. Receptors for insulin-like growth factors I and II: autoradiographic localization in rat brain and comparison to receptors for insulin

    International Nuclear Information System (INIS)

    Lesniak, M.A.; Hill, J.M.; Kiess, W.; Rojeski, M.; Pert, C.B.; Roth, J.

    1988-01-01

    Receptors for insulin-like growth factor I (IGF-I) in rat brain were visualized using autoradiography with [125I]IGF-I. The binding of the labeled peptide was competed for fully by high concentrations of unlabeled IGF-I. At intermediate concentrations of unlabeled peptide the binding of [125I]IGF-I was competed for by unlabeled IGF-I more effectively than by IGF-II or insulin, which is typical of receptors for IGF-I. Essentially every brain section shows specific binding of IGF-I, and the pattern of binding of IGF-I to its receptors correlated well with the cytoarchitectonic structures. In parallel studies we showed that [125I]IGF-II was bound to tissue sections of rat brain and that the binding was competed for by an excess of unlabeled IGF-II. However, intermediate concentrations of unlabeled peptides gave inconclusive results. To confirm that the binding of [125I]IGF-II was to IGF-II receptors, we showed that antibodies specific for the IGF-II receptor inhibited the binding of labeled IGF-II. Furthermore, the binding of the antibody to regions of the brain section, visualized by the application of [125I]protein-A, gave patterns indistinguishable from those obtained with [125I]IGF-II alone. Again, the binding was very widely distributed throughout the central nervous system, and the patterns of distribution corresponded well to the underlying neural structures. Densitometric analysis of the receptors enabled us to compare the distribution of IGF-I receptors with that of IGF-II receptors as well as retrospectively with that of insulin receptors

  19. Inhibition of type I insulin-like growth factor receptor signaling attenuates the development of breast cancer brain metastasis.

    Directory of Open Access Journals (Sweden)

    Sandra M Saldana

    Full Text Available Brain metastasis is a common cause of mortality in cancer patients, yet potential therapeutic targets remain largely unknown. The type I insulin-like growth factor receptor (IGF-IR is known to play a role in the progression of breast cancer and is currently being investigated in the clinical setting for various types of cancer. The present study demonstrates that IGF-IR is constitutively autophosphorylated in brain-seeking breast cancer sublines. Knockdown of IGF-IR results in a decrease of phospho-AKT and phospho-p70s6k, as well as decreased migration and invasion of MDA-MB-231Br brain-seeking cells. In addition, transient ablation of IGFBP3, which is overexpressed in brain-seeking cells, blocks IGF-IR activation. Using an in vivo experimental brain metastasis model, we show that IGF-IR knockdown brain-seeking cells have reduced potential to establish brain metastases. Finally, we demonstrate that the malignancy of brain-seeking cells is attenuated by pharmacological inhibition with picropodophyllin, an IGF-IR-specific tyrosine kinase inhibitor. Together, our data suggest that the IGF-IR is an important mediator of brain metastasis and its ablation delays the onset of brain metastases in our model system.

  20. Divergent frequencies of IGF-I receptor-expressing blood lymphocytes in monozygotic twin pairs discordant for Graves' disease: evidence for a phenotypic signature ascribable to nongenetic factors

    DEFF Research Database (Denmark)

    Douglas, Raymond S; Brix, Thomas H; Hwang, Catherine J

    2009-01-01

    CONTEXT: Graves' disease (GD) is an autoimmune process of the thyroid and orbital connective tissues. The fraction of T and B cells expressing IGF-I receptor (IGF-IR) is increased in GD. It is a potentially important autoantigen in GD. Susceptibility to GD arises from both genetic and acquired...... factors. OBJECTIVE: The aim of the study was to determine whether the increased frequency of IGF-IR-expressing T and B cells in GD results from genetic or nongenetic factors. DESIGN/SETTING/PARTICIPANts: Display of IGF-IR was assessed on blood lymphocytes from 18 pairs of monozygotic twins in the Danish...

  1. Mammary tumors that become independent of the type I insulin-like growth factor receptor express elevated levels of platelet-derived growth factor receptors

    Directory of Open Access Journals (Sweden)

    Campbell Craig I

    2011-11-01

    Full Text Available Abstract Background Targeted therapies are becoming an essential part of breast cancer treatment and agents targeting the type I insulin-like growth factor receptor (IGF-IR are currently being investigated in clinical trials. One of the limitations of targeted therapies is the development of resistant variants and these variants typically present with unique gene expression patterns and characteristics compared to the original tumor. Results MTB-IGFIR transgenic mice, with inducible overexpression of the IGF-IR were used to model mammary tumors that develop resistance to IGF-IR targeting agents. IGF-IR independent mammary tumors, previously shown to possess characteristics associated with EMT, were found to express elevated levels of PDGFRα and PDGFRβ. Furthermore, these receptors were shown to be inversely expressed with the IGF-IR in this model. Using cell lines derived from IGF-IR-independent mammary tumors (from MTB-IGFIR mice, it was demonstrated that PDGFRα and to a lesser extent PDGFRβ was important for cell migration and invasion as RNAi knockdown of PDGFRα alone or PDGFRα and PDGFRβ in combination, significantly decreased tumor cell migration in Boyden chamber assays and suppressed cell migration in scratch wound assays. Somewhat surprisingly, concomitant knockdown of PDGFRα and PDGFRβ resulted in a modest increase in cell proliferation and a decrease in apoptosis. Conclusion During IGF-IR independence, PDGFRs are upregulated and function to enhance tumor cell motility. These results demonstrate a novel interaction between the IGF-IR and PDGFRs and highlight an important, therapeutically relevant pathway, for tumor cell migration and invasion.

  2. Transforming growth factor-β-stimulated clone-22 (TSC-22) is an androgen regulated gene that enhances apoptosis in prostate cancer following IGF-IR inhibition

    Science.gov (United States)

    Sprenger, Cynthia C. T.; Haugk, Kathleen; Sun, Shihua; Coleman, Ilsa; Nelson, Peter S.; Vessella, Robert L.; Ludwig, Dale L.; Wu, Jennifer D.; Plymate, Stephen R.

    2009-01-01

    Purpose Inhibition of IGF signaling using the human IGF-IR monoclonal antibody A12 is most effective at inducing apoptosis in prostate cancer xenografts in the presence of androgen. We undertook this study to determine mechanisms for increased apoptosis by A12 in the presence of androgens. Experimental Methods The castrate-resistant human xenograft LuCaP 35V was implanted into intact or castrate SCID mice and treated with A12 weekly. After six weeks of tumor growth animals were sacrificed and tumors removed and analyzed for cell cycle distribution/apoptosis and cDNA arrays were performed. Results In castrate mice the tumors were delayed in G2 with no apoptosis; in contrast tumors from intact mice underwent apoptosis with either a G1 or G2 delay. TSC-22 was significantly elevated in tumors from the intact mice compared to castrate mice, especially in those tumors with the highest levels of apoptosis. In order to further determine the function of TSC-22, we transfected various human prostate cancer cell lines with a plasmid expressing TSC-22. Cell lines overexpressing TSC-22 demonstrated an increase in apoptosis and a delay in G1. When these cell lines were placed subcutaneously in SCID mice a decreased number of animals formed tumors and the rate of tumor growth was decreased compared to control tumors. Conclusions These data indicate that IGF-IR inhibition in the presence of androgen has an enhanced effect on decreasing tumor growth, in part, through increased expression of the tumor suppressor gene TSC-22. PMID:19996218

  3. Surface-expressed insulin receptors as well as IGF-I receptors both contribute to the mitogenic effects of human insulin and its analogues

    DEFF Research Database (Denmark)

    Lundby, Anders; Bolvig, Pernille; Hegelund, Anne Charlotte

    2015-01-01

    There is a medical need for new insulin analogues. Yet, molecular alterations to the insulin molecule can theoretically result in analogues with carcinogenic effects. Preclinical carcinogenicity risk assessment for insulin analogues rests to a large extent on mitogenicity assays in cell lines. We...... therefore optimized mitogenicity assay conditions for a panel of five cell lines. All cell lines expressed insulin receptors (IR), IGF-I receptors (IGF-IR) and hybrid receptors, and in all cell lines, insulin as well as the comparator compounds X10 and IGF-I caused phosphorylation of the IR as well as IGF......-IR. Insulin exhibited mitogenicity EC50 values in the single-digit nanomolar to picomolar range. We observed correlations across cell types between (i) mitogenic potency of insulin and IGF-IR/IR ratio, (ii) Akt phosphorylation and mitogenic potency and (iii) Akt phosphorylation and IR phosphorylation. Using...

  4. Cytokines and soluble tumour necrosis factor I receptor levels during pretransplant conditioning in allogeneic stem-cell transplantation

    DEFF Research Database (Denmark)

    Andersen, Johnny; Heilmann, Carsten; Jacobsen, Niels

    2005-01-01

    a broad range of cytokines in plasma samples drawn daily immediately before start of pretransplant conditioning and during the conditioning. The presented data indicate that single-day measurements of inflammatory cytokines during conditioning may lead to unreliable conclusions concerning their prognostic...... significance. However, serial quantitation of soluble tumour necrosis factor receptor I (sTNFRI) is more likely to reflect the degree of inflammatory activation induced by pretransplant conditioning....

  5. Increased abundance of insulin/insulin-like growth factor-I hybrid receptors in skeletal muscle of obese subjects is correlated with in vivo insulin sensitivity.

    Science.gov (United States)

    Federici, M; Porzio, O; Lauro, D; Borboni, P; Giovannone, B; Zucaro, L; Hribal, M L; Sesti, G

    1998-08-01

    We reported that in noninsulin-dependent diabetes melitus (NIDDM) patients expression of insulin/insulin-like growth factor I (IGF-I) hybrid receptors is increased in insulin target tissues. Whether this is a defect associated with NIDDM or represents a generalized abnormality associated with insulin resistant states is still unsettled. To address this, we applied a microwell-based immunoassay to measure abundance of insulin receptors, type 1 IGF receptors, and hybrid receptors in muscle of eight normal and eight obese subjects. Maximal insulin binding to insulin receptors was lower in obese than in control subjects (B/T = 1.8 +/- 0.20 and 2.6 +/- 0.30; P < 0.03, respectively) and was negatively correlated with insulinemia (r = -0.60; P < 0.01). Maximal IGF-I binding to type 1 IGF receptors was higher in obese than in controls (B/T = 1.9 +/- 0.20 and 0.86 +/- 0.10; P < 0.0001, respectively) and was negatively correlated with plasma IGF-I levels (r = -0.69; P < 0.003). Hybrid receptor abundance was higher in obese than in normal subjects (B/T = 1.21 +/- 0.14 and 0.44 +/- 0.06; P < 0.0003, respectively) and was negatively correlated with insulin binding (r = -0.60; P < 0.01) and positively correlated with IGF-I binding (r = 0.92; P < 0.0001). Increased abundance of hybrids was correlated with insulinemia (r = 0.70; P < 0.002) and body mass index (r = 0.71; P < 0.0019), whereas it was negatively correlated with in vivo insulin sensitivity measured by ITT (r = -0.67; P < 0.016). These results indicate that downregulation of insulin receptors or upregulation of type 1 IGF receptors because of changes in plasma insulin and IGF-I levels may result in modifications in hybrid receptor abundance.

  6. Development of receptors for insulin and insulin-like growth factor-I in head and brain of chick embryos: Autoradiographic localization

    International Nuclear Information System (INIS)

    Bassas, L.; Girbau, M.; Lesniak, M.A.; Roth, J.; de Pablo, F.

    1989-01-01

    In whole brain of chick embryos insulin receptors are highest at the end of embryonic development, while insulin-like growth factor-I (IGF-I) receptors dominate in the early stages. These studies provided evidence for developmental regulation of both types of receptors, but they did not provide information on possible differences between brain regions at each developmental stage or within one region at different embryonic ages. We have now localized the specific binding of [125I]insulin and [125I]IGF-I in sections of head and brain using autoradiography and computer-assisted densitometric analysis. Embryos have been studied from the latter part of organogenesis (days 6 and 12) through late development (day 18, i.e. 3 days before hatching), and the binding patterns have been compared with those in the adult brain. At all ages the binding of both ligands was to discrete anatomical regions. Interestingly, while in late embryos and adult brain the patterns of [125I]insulin and [125I] IGF-I binding were quite distinct, in young embryos both ligands showed very similar localization of binding. In young embryos the retina and lateral wall of the growing encephalic vesicles had the highest binding of both [125I]insulin and [125I]IGF-I. In older embryos, as in the adult brain, insulin binding was high in the paleostriatum augmentatum and molecular layer of the cerebellum, while IGF-I binding was prominent in the hippocampus and neostriatum. The mapping of receptors in a vertebrate embryo model from early prenatal development until adulthood predicts great overlap in any possible function of insulin and IGF-I in brain development, while it anticipates differential localized actions of the peptides in the mature brain

  7. Characterization of insulin-like growth factor I and insulin receptors on cultured bovine adrenal fasciculata cells. Role of these peptides on adrenal cell function

    International Nuclear Information System (INIS)

    Penhoat, A.; Chatelain, P.G.; Jaillard, C.; Saez, J.M.

    1988-01-01

    We have characterized insulin-like growth factor I (IGF-I) and insulin receptors in cultured bovine adrenal cells by binding and cross-linking affinity experiments. At equilibrium the dissociation constant and the number of binding sites per cell for IGF-I were 1.4 +/- (SE) 0.3 x 10(-9) M and 19,200 +/- 2,100, respectively. Under reduction conditions, disuccinimidyl suberate cross-linked [ 125 I]iodo-IGF-I to one receptor complex with an Mr of 125,000. Adrenal cells also contain specific insulin receptors with an apparent dissociation constant (Kd) of 10(-9) M. Under reduction conditions [ 125 I]iodo-insulin binds to one band with an approximate Mr of 125,000. IGF-I and insulin at micromolar concentrations, but not at nanomolar concentrations, slightly stimulated DNA synthesis, but markedly potentiated the mitogenic action of fibroblast growth factor. Adrenal cells cultured in a serum-free medium containing transferrin, ascorbic acid, and insulin (5 micrograms/ml) maintained fairly constant angiotensin-II (A-II) receptor concentration per cell and increased cAMP release on response to ACTH and their steroidogenic response to both ACTH and A-II. When the cells were cultured in the same medium without insulin, the number of A-II receptors significantly decreased to 65% and the increased responsiveness was blunted. Treatment of such cells for 3 days with increasing concentrations of IGF-I (1-100 ng/ml) produced a 2- to 3-fold increase in A-II receptors and enhanced the cAMP response (3- to 4-fold) to ACTH and the steroidogenic response (4- to 6-fold) to ACTH and A-II. These effects were time and dose dependent (ED50 approximately equal to 10(-9) M). Insulin at micromolar concentrations produced an effect similar to that of IGF-I, but at nanomolar concentrations the effect was far less

  8. Testosterone enables growth and hypertrophy in fusion impaired myoblasts that display myotube atrophy: deciphering the role of androgen and IGF-I receptors.

    Science.gov (United States)

    Hughes, David C; Stewart, Claire E; Sculthorpe, Nicholas; Dugdale, Hannah F; Yousefian, Farzad; Lewis, Mark P; Sharples, Adam P

    2016-06-01

    We have previously highlighted the ability of testosterone (T) to improve differentiation and myotube hypertrophy in fusion impaired myoblasts that display reduced myotube hypertrophy via multiple population doublings (PD) versus their parental controls (CON); an observation which is abrogated via PI3K/Akt inhibition (Deane et al. 2013). However, whether the most predominant molecular mechanism responsible for T induced hypertrophy occurs directly via androgen receptor or indirectly via IGF-IR/PI3K/Akt pathway is currently debated. PD and CON C2C12 muscle cells were exposed to low serum conditions in the presence or absence of T (100 nM) ± inhibitors of AR (flutamide/F, 40 μm) and IGF-IR (picropodophyllin/PPP, 150 nM) for 72 h and 7 days (early/late muscle differentiation respectively). T increased AR and Akt abundance, myogenin gene expression, and myotube hypertrophy, but not ERK1/2 activity in both CON and PD cell types. Akt activity was not increased significantly in either cell type with T. Testosterone was also unable to promote early differentiation in the presence of IGF-IR inhibitor (PPP) yet still able to promote appropriate later increases in myotube hypertrophy and AR abundance despite IGF-IR inhibition. The addition of the AR inhibitor powerfully attenuated all T induced increases in differentiation and myotube hypertrophy with corresponding reductions in AR abundance, phosphorylated Akt, ERK1/2 and gene expression of IGF-IR, myoD and myogenin with increases in myostatin mRNA in both cell types. Interestingly, despite basally reduced differentiation and myotube hypertrophy, PD cells showed larger T induced increases in AR abundance vs. CON cells, a response abrogated in the presence of AR but not IGF-IR inhibitors. Furthermore, T induced increases in Akt abundance were sustained despite the presence of IGF-IR inhibition in PD cells only. Importantly, flutamide alone reduced IGF-IR mRNA in both cell types across time points, with an observed

  9. Characterization of insulin-like growth factor I receptors in the median eminence of the brain and their modulation by food restriction

    International Nuclear Information System (INIS)

    Bohannon, N.J.; Corp, E.S.; Wilcox, B.J.; Figlewicz, D.P.; Dorsa, D.M.; Baskin, D.G.

    1988-01-01

    High affinity binding sites for 125I-labeled [Thr59]insulin-like growth factor I (IGF-I) were measured in rat median eminence by in vitro autoradiography with slide-mounted sections of frozen rat brain. Specific binding of 0.1 nM iodo-[Thr59]IGF-I to brain slices reached maximum by 12 h at 4 C and was unchanged at 24 h. Densitometry by computer digital image analysis of autoradiographic images indicated that specific binding of iodo-[Thr59]IGF-I to the median eminence was reversible. The specificity of binding was evaluated with competition of iodo-[Thr59]IGF-I with unlabeled [Thr59]IGF-I, rat IGF-II (multiplication-stimulating activity), and porcine insulin. All were recognized by the binding site, but the rank order of potency was [Thr59]IGF-I greater than IGF-II greater than insulin. Somatostatin was completely ineffective. Further, an antibody against the rat IGF-II receptor did not block binding of iodo-[Thr59]IGF-I to the median eminence. Fourteen days of food restriction (75% of food intake of controls) resulted in significant weight loss and reduction of plasma immunoreactive IGF-I in six food-restricted rats (0.9 +/- 0.1 U/ml) compared with values in six controls (2.6 +/- 0.5 U/ml; P less than 0.001). Binding of 125I-labeled [Thr59]IGF-I in the median eminence was significantly increased in the food-restricted rats, primarily due to an increase in the concentration of iodo-[Thr59]IGF-I-binding sites in the median eminence; the affinity (Kd) of binding was unchanged. The results indicate that the median eminence has type I IGF-I receptors, which become more numerous under metabolic conditions associated with decreased caloric intake and lowered plasma IGF-I levels

  10. 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

  11. Role of receptors for epidermal growth factor and insulin-like growth factors I and II in the differentiation of rat mammary glands from lactogenesis I to lactogenesis II.

    Science.gov (United States)

    Bussmann, L E; Bussmann, I M; Charreau, E H

    1996-07-01

    In addition to ovarian steroids and lactogenic hormones from the placenta and pituitary, growth factors control the growth and differentiation of mammary glands. Lactogenesis II at the end of pregnancy is under the control of progesterone. Ovariectomy results in a significant decrease in the number of receptors for epidermal growth factor (EGF) and insulin-like growth factor I (IGF-I) and an increase in IGF-II binding sites in mammary gland acini of rats, without affecting the affinity for their respective ligand. Although concentrations of EGF, IGF-I and IGF-II receptors are regulated by oestradiol and progesterone, replacement treatment with ovarian steroids after ovariectomy showed that receptor concentrations do not mediate the restraint on lactogenesis. Progesterone treatment, which inhibits the onset of lactogenesis II, did not restore EGF receptor concentrations to control values, and the presence of oestradiol was required to reverse the effect of ovariectomy. Oestradiol, which potentiates the effect of ovariectomy on milk synthesis, increases IGF-I receptor concentrations. IGF-II receptor concentrations, after the different steroid treatments, were consistent with the steroid effect on milk synthesis. The changes observed in the concentrations of these growth factor receptors at the onset of mammary gland secretion are not considered to affect the progesterone block to lactogenesis II, but rather are a consequence of the shift of the hormonal and, hence, physiological status of the gland.

  12. 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.

  13. INSULIN ANALOGUES: ANALYSIS OF PROLIFERATIVE POTENCY AND CHARACTERIZATION OF RECEPTORS AND SIGNALLING PATHWAYS ACTIVATED IN HUMAN MAMMARY EPITHELIAL CELLS

    OpenAIRE

    Shukla, Ashish

    2009-01-01

    Insulin analogues have been developed with the aim to provide better glycaemic control to diabetic patients. They are generated by modifying the insulin backbone which, however, may alter relevant biochemical characteristics such as the affinity to insulin receptor and type I insulin-like growth factor receptor (IGF-IR), and the insulin receptor dissociation rate. As a result insulin analogues may exhibit stronger mitogenic potency than regular insulin. Normal mammary epithelial cells show hi...

  14. Retroviral expression of a kinase-defective IGF-I receptor suppresses growth and causes apoptosis of CHO and U87 cells in-vivo

    International Nuclear Information System (INIS)

    Seely, B Lynn; Samimi, Goli; Webster, Nicholas JG

    2002-01-01

    Phosphatidylinositol-3,4,5-triphosphate (PtdInsP3) signaling is elevated in many tumors due to loss of the tumor suppressor PTEN, and leads to constitutive activation of Akt, a kinase involved in cell survival. Reintroduction of PTEN in cells suppresses transformation and tumorigenicity. While this approach works in-vitro, it may prove difficult to achieve in-vivo. In this study, we investigated whether inhibition of growth factor signaling would have the same effect as re-expression of PTEN. Dominant negative IGF-I receptors were expressed in CHO and U87 cells by retroviral infection. Cell proliferation, transformation and tumor formation in athymic nude mice were assessed. Inhibition of IGF-IR signaling in a CHO cell model system by expression of a kinase-defective IGF-IR impairs proliferation, transformation and tumor growth. Reduction in tumor growth is associated with an increase in apoptosis in-vivo. The dominant-negative IGF-IRs also prevented growth of U87 PTEN-negative glioblastoma cells when injected into nude mice. Injection of an IGF-IR blocking antibody αIR3 into mice harboring parental U87 tumors inhibits tumor growth and increases apoptosis. Inhibition of an upstream growth factor signal prevents tumor growth of the U87 PTEN-deficient glioma to the same extent as re-introduction of PTEN. This result suggests that growth factor receptor inhibition may be an effective alternative therapy for PTEN-deficient tumors

  15. Systemic administration of kainic acid induces selective time dependent decrease in [125I]insulin-like growth factor I, [125I]insulin-like growth factor II and [125I]insulin receptor binding sites in adult rat hippocampal formation

    International Nuclear Information System (INIS)

    Quirion, R.; Chabot, J.-G.; Dore, S.; Seto, D.; Kar, S.

    1997-01-01

    Administration of kainic acid evokes acute seizure in hippocampal pathways that results in a complex sequence of functional and structural alterations resembling human temporal lobe epilepsy. The structural alterations induced by kainic acid include selective loss of neurones in CA1-CA3 subfields and the hilar region of the dentate gyrus followed by sprouting and permanent reorganization of the synaptic connections of the mossy fibre pathways. Although the neuronal degeneration and process of reactive synaptogenesis have been extensively studied, at present little is known about means to prevent pathological conditions leading to kainate-induced cell death. In the present study, to address the role of insulin-like growth factors I and II, and insulin in neuronal survival as well as synaptic reorganization following kainate-induced seizure, the time course alterations of the corresponding receptors were evaluated. Additionally, using histological preparations, the temporal profile of neuronal degeneration and hypertrophy of resident astroglial cells were also studied. [ 125 I]Insulin-like growth factor I binding was found to be decreased transiently in almost all regions of the hippocampal formation at 12 h following treatment with kainic acid. The dentate hilar region however, exhibited protracted decreases in [ 125 I]insulin-like growth factor I receptor sites throughout (i.e. 30 days) the study. [ 125 I]Insulin-like growth factor II receptor binding sites in the hippocampal formation were found to be differentially altered following systemic administration of kainic acid. A significant decrease in [ 125 I]insulin-like growth factor II receptor sites was observed in CA1 subfield and the pyramidal cell layer of the Ammon's horn at all time points studied whereas the hilar region and the stratum radiatum did not exhibit alteration at any time. A kainate-induced decrease in [ 125 I]insulin receptor binding was noted at all time points in the molecular layer of the

  16. Anti-tumor effect in human breast cancer by TAE226, a dual inhibitor for FAK and IGF-IR in vitro and in vivo

    Energy Technology Data Exchange (ETDEWEB)

    Kurio, Naito [Department of Oral and Maxillofacial Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, 700-8525 (Japan); Shimo, Tsuyoshi, E-mail: shimotsu@md.okayama-u.ac.jp [Department of Oral and Maxillofacial Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, 700-8525 (Japan); Fukazawa, Takuya; Takaoka, Munenori [Department of General Surgery, Kawasaki Medical School, Okayama, 700-0821 (Japan); Okui, Tatsuo; Hassan, Nur Mohammad Monsur; Honami, Tatsuki [Department of Oral and Maxillofacial Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, 700-8525 (Japan); Hatakeyama, Shinji [Novartis Institutes for BioMedical Research, Basel (Switzerland); Ikeda, Masahiko [Department of Surgery, Fukuyama City Hospital, Fukuyama, 720-8511 (Japan); Naomoto, Yoshio [Department of General Surgery, Kawasaki Medical School, Okayama, 700-0821 (Japan); Sasaki, Akira [Department of Oral and Maxillofacial Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, 700-8525 (Japan)

    2011-05-01

    Focal adhesion kinase (FAK) is a 125-kDa non-receptor type tyrosine kinase that localizes to focal adhesions. FAK overexpression is frequently found in invasive and metastatic cancers of the breast, colon, thyroid, and prostate, but its role in osteolytic metastasis is not well understood. In this study, we have analyzed anti-tumor effects of the novel FAK Tyr{sup 397} inhibitor TAE226 against bone metastasis in breast cancer by using TAE226. Oral administration of TAE226 in mice significantly decreased bone metastasis and osteoclasts involved which were induced by MDA-MB-231 breast cancer cells and increased the survival rate of the mouse models of bone metastasis. TAE226 also suppressed the growth of subcutaneous tumors in vivo and the proliferation and migration of MDA-MB-231 cells in vitro. Significantly, TAE226 inhibited the osteoclast formation in murine pre-osteoclastic RAW264.7 cells, and actin ring and pit formation in mature osteoclasts. Moreover, TAE226 inhibited the receptor activator for nuclear factor {kappa} B Ligand (RANKL) gene expression induced by parathyroid hormone-related protein (PTHrP) in bone stromal ST2 cells and blood free calcium concentration induced by PTHrP administration in vivo. These findings suggest that FAK was critically involved in osteolytic metastasis and activated in tumors, pre-osteoclasts, mature osteoclasts, and bone stromal cells and TAE226 can be effectively used for the treatment of cancer induced bone metastasis and other bone diseases.

  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. A peptide from Porphyra yezoensis stimulates the proliferation of IEC-6 cells by activating the insulin-like growth factor I receptor signaling pathway.

    Science.gov (United States)

    Lee, Min-Kyeong; Kim, In-Hye; Choi, Youn-Hee; Nam, Taek-Jeong

    2015-02-01

    Porphyra yezoensis (P. yezoensis) is the most noteworthy red alga and is mainly consumed in China, Japan and Korea. In the present study, the effects of a P. yezoensis peptide (PY‑PE) on cell proliferation and the associated signaling pathways were examined in IEC‑6 rat intestinal epithelial cells. First, the MTS assay showed that PY‑PE induced cell proliferation in a dose‑dependent manner. Subsequently, the mechanism behind the proliferative activity induced by PY‑PE was determined. The insulin‑like growth factor‑I receptor (IGF‑IR) signaling pathway was the main focus as it plays an important role in the regulation of cell growth and proliferation. PY‑PE increased the protein and mRNA expression of IGF‑IR, insulin receptor substrate‑1, Shc and PY‑99. In addition, PY‑PE stimulated extracellular signal‑regulated kinase phosphorylation and phosphatidylinositol 3‑kinase/Akt activation but inhibited p38 and c‑Jun N‑terminal kinase phosphorylation. Furthermore, PY‑PE treatment increased protein and mRNA expression levels of activator protein‑1, which regulates cell proliferation and survival, in the nuclear fraction. These results have significant implications for understanding the role of cell proliferation signaling pathways in intestinal epithelial cells.

  19. Impact of the growth hormone receptor exon 3 deletion gene polymorphism on glucose metabolism, lipids, and insulin-like growth factor-I levels during puberty

    DEFF Research Database (Denmark)

    Sørensen, Kaspar; Aksglaede, Lise; Munch-Andersen, Thor

    2009-01-01

    the impact of the GHRd3 gene polymorphism on insulin sensitivity, insulin secretion, lipids, and IGF-I levels in healthy children and adolescents. DESIGN: This was cross-sectional and was part of the COPENHAGEN puberty study. SETTING: The study was conducted at a tertiary center for pediatric endocrinology......-I levels. RESULTS: Insulin secretion was higher in children and adolescents with a least one GHRd3 allele, even after adjustment for age, sex, pubertal stage, and insulin sensitivity (P = 0.018). Disposition index was higher in GHRd3-positive subjects (P = 0.026). In addition, the GHRd3 allele......CONTEXT: The GH/IGF-I axis has major impact on insulin sensitivity and insulin secretion. Recently a polymorphism in the GH receptor gene (GHR), a genomic deletion of exon 3 (GHRd3), has been linked to increased responsiveness to GH. OBJECTIVE: The objective of the present study was to evaluate...

  20. Insulin-Like Growth Factor I Produces an Antidepressant-Like Effect and Elicits N-Methyl-D-Aspartate Receptor Independent Long-Term Potentiation of Synaptic Transmission in Medial Prefrontal Cortex and Hippocampus.

    Science.gov (United States)

    Burgdorf, Jeffrey; Zhang, Xiao-lei; Colechio, Elizabeth M; Ghoreishi-Haack, Nayereh; Gross, Amanda; Kroes, Roger A; Stanton, Patric K; Moskal, Joseph R

    2015-09-15

    Growth factors play an important role in regulating neurogenesis and synapse formation and may be involved in regulating the antidepressant response to conventional antidepressants. To date, Insulin-like growth factor I (IGFI) is the only growth factor that has shown antidepressant properties in human clinical trials. However, its mechanism of action remains unclear. The antidepressant-like effect of a single IV dose of IGFI was determined using a chronic unpredictable stress paradigm in the rat Porsolt, sucrose preference, novelty-induced hypophagia, and ultrasonic vocalization models. The dependence of the medial prefrontal cortex for these effects was determined by direct medial prefrontal cortex injection followed by Porsolt testing as well as IGFI receptor activation in the medial prefrontal cortex following an optimal IV antidepressant-like dose of IGFI. The effect of IGFI on synaptic transmission and long-term potentiation (LTP) of synaptic strength was assessed in the hippocampus and medial prefrontal cortex. The dependence of these effects on IGFI and AMPA receptor activation and protein synthesis were also determined. IGFI produced a rapid-acting and long-lasting antidepressant-like effect in each of the depression models. These effects were blocked by IGFI and AMPA receptor antagonists, and medial prefrontal cortex was localized. IGFI robustly increased synaptic strength in the hippocampus and medial prefrontal cortex and these effects were IGFI receptor and protein synthesis-dependent but N-methyl-d-aspartate receptor independent. IGFI also robustly facilitated hippocampal metaplasticity 24 hours postdosing. These data support the conclusion that the antidepressant-like effects of IGFI are mediated by a persistent, LTP-like enhancement of synaptic strength requiring both IGFIR activation and ongoing protein synthesis. © The Author 2015. Published by Oxford University Press on behalf of CINP.

  1. Glucocorticoids facilitate the transcription from the human cytomegalovirus major immediate early promoter in glucocorticoid receptor- and nuclear factor-I-like protein-dependent manner

    International Nuclear Information System (INIS)

    Inoue-Toyoda, Maki; Kato, Kohsuke; Nagata, Kyosuke; Yoshikawa, Hiroyuki

    2015-01-01

    Human cytomegalovirus (HCMV) is a common and usually asymptomatic virus agent in healthy individuals. Initiation of HCMV productive infection depends on expression of the major immediate early (MIE) genes. The transcription of HCMV MIE genes is regulated by a diverse set of transcription factors. It was previously reported that productive HCMV infection is triggered probably by elevation of the plasma hydroxycorticoid level. However, it is poorly understood whether the transcription of MIE genes is directly regulated by glucocorticoid. Here, we found that the dexamethasone (DEX), a synthetic glucocorticoid, facilitates the transcription of HCMV MIE genes through the MIE promoter and enhancer in a glucocorticoid receptor (GR)-dependent manner. By competitive EMSA and reporter assays, we revealed that an NF-I like protein is involved in DEX-mediated transcriptional activation of the MIE promoter. Thus, this study supports a notion that the increased level of hydroxycorticoid in the third trimester of pregnancy reactivates HCMV virus production from the latent state. - Highlights: • DEX facilitates the transcription from the HCMV MIE promoter. • GR is involved in DEX-dependent transcription from the HCMV MIE promoter. • A 17 bp repeat is responsible for the HCMV MIE promoter activation by DEX. • An NF-I-like protein is involved in the HCMV MIE promoter activation by DEX

  2. Glucocorticoids facilitate the transcription from the human cytomegalovirus major immediate early promoter in glucocorticoid receptor- and nuclear factor-I-like protein-dependent manner

    Energy Technology Data Exchange (ETDEWEB)

    Inoue-Toyoda, Maki [Graduate School of Comprehensive Human Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba 305-8575 (Japan); Kato, Kohsuke [Graduate School of Comprehensive Human Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba 305-8575 (Japan); Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba 305-8575 (Japan); Nagata, Kyosuke, E-mail: knagata@md.tsukuba.ac.jp [University of Tsukuba, 1-1-1 Tennodai, Tsukuba 305-8575 (Japan); Yoshikawa, Hiroyuki [Graduate School of Comprehensive Human Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba 305-8575 (Japan); Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba 305-8575 (Japan)

    2015-02-27

    Human cytomegalovirus (HCMV) is a common and usually asymptomatic virus agent in healthy individuals. Initiation of HCMV productive infection depends on expression of the major immediate early (MIE) genes. The transcription of HCMV MIE genes is regulated by a diverse set of transcription factors. It was previously reported that productive HCMV infection is triggered probably by elevation of the plasma hydroxycorticoid level. However, it is poorly understood whether the transcription of MIE genes is directly regulated by glucocorticoid. Here, we found that the dexamethasone (DEX), a synthetic glucocorticoid, facilitates the transcription of HCMV MIE genes through the MIE promoter and enhancer in a glucocorticoid receptor (GR)-dependent manner. By competitive EMSA and reporter assays, we revealed that an NF-I like protein is involved in DEX-mediated transcriptional activation of the MIE promoter. Thus, this study supports a notion that the increased level of hydroxycorticoid in the third trimester of pregnancy reactivates HCMV virus production from the latent state. - Highlights: • DEX facilitates the transcription from the HCMV MIE promoter. • GR is involved in DEX-dependent transcription from the HCMV MIE promoter. • A 17 bp repeat is responsible for the HCMV MIE promoter activation by DEX. • An NF-I-like protein is involved in the HCMV MIE promoter activation by DEX.

  3. 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......, transitory (liver IGF-I mRNA levels after SW transfer, suggesting that decreased plasma levels...... 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...

  4. 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.

  5. Chronic alterations in growth hormone/insulin-like growth factor-I signaling lead to changes in mouse tendon structure

    DEFF Research Database (Denmark)

    Nielsen, R H; Clausen, N M; Schjerling, P

    2014-01-01

    RNA expression (targets: GAPDH, RPLP0, IGF-IEa, IGF-IR, COL1A1, COL3A1, TGF-β1, TGF-β2, TGF-β3, versican, scleraxis, tenascin C, fibronectin, fibromodulin, decorin) in the Achilles tendon, and the mRNA expression was also measured in calf muscle (same targets as tendon plus IGF-IEb, IGF-IEc). We found that GHR......The growth hormone/insulin-like growth factor-I (GH/IGF-I) axis is an important stimulator of collagen synthesis in connective tissue, but the effect of chronically altered GH/IGF-I levels on connective tissue of the muscle-tendon unit is not known. We studied three groups of mice; 1) giant......-/- mice had significantly lower collagen fibril volume fraction in Achilles tendon, as well as decreased mRNA expression of IGF-I isoforms and collagen types I and III in muscle compared to CTRL. In contrast, the mRNA expression of IGF-I isoforms and collagens in bGH mice was generally high in both tendon...

  6. Insulin analogues and cancer: a note of caution

    Directory of Open Access Journals (Sweden)

    Joseph A.M.J.L. eJanssen

    2014-05-01

    Full Text Available Abstract In view of the lifelong exposure and large patient populations involved, insulin analogues with an increased mitogenic effect in comparison to human insulin may potentially constitute a major health problem, since these analogues may possibly induce the growth of pre-existing neoplasms. At present, the available data suggest that insulin analogues are safe. In line with these findings, we observed that serum of diabetic patients treated with insulin analogues, compared to that of diabetic patients treated with human insulin, did not induce an increased phosphorylation of tyrosine residues of the insulin-like growth factor-I receptor (IGF-IR. However, the classical model of the IGF-IR signaling may be insufficient to explain (all mitogenic effects of insulin analogues since also non-canonical signaling pathways of the IGF-IR may play a major role in this respect. Although phosphorylation of tyrosine residues of the IGF-IR is generally considered to be the initial activation step within the intracellular IGF-IR signaling pathway, it has been found that cells undergo a signaling switch under hyperglycemic conditions. After this switch, a completely different mechanism is utilized to activate the mitogenic (mitogen-activated protein kinase (MAPK pathways of the IGF-IR that is independent from tyrosine phosphorylation of the IGF-IR. At present it is unknown whether activation of this alternative intracellular pathway of the IGF-IR occurs during hyperglycemia in vivo and whether it is stronger in patients treated with (some insulin analogues than in patients treated with human insulin. In addition, it is unknown whether the insulin receptors (IRs also undergo a signaling switch during hyperglycemia. This should be investigated in future studies. Finally, relative overexpression of IR isoform A (IR-A in (pre cancer tissues may play a key role in the development and progression of human cancers during treatment with insulin (analogues. Further

  7. Increased oxidative stress and apoptosis in the hypothalamus of diabetic male mice in the insulin receptor substrate-2 knockout model.

    Science.gov (United States)

    Baquedano, Eva; Burgos-Ramos, Emma; Canelles, Sandra; González-Rodríguez, Agueda; Chowen, Julie A; Argente, Jesús; Barrios, Vicente; Valverde, Angela M; Frago, Laura M

    2016-05-01

    Insulin receptor substrate-2-deficient (IRS2(-/-)) mice are considered a good model to study the development of diabetes because IRS proteins mediate the pleiotropic effects of insulin-like growth factor-I (IGF-I) and insulin on metabolism, mitogenesis and cell survival. The hypothalamus might play a key role in the early onset of diabetes, owing to its involvement in the control of glucose homeostasis and energy balance. Because some inflammatory markers are elevated in the hypothalamus of diabetic IRS2(-/-) mice, our aim was to analyze whether the diabetes associated with the absence of IRS2 results in hypothalamic injury and to analyze the intracellular mechanisms involved. Only diabetic IRS2(-/-) mice showed increased cell death and activation of caspase-8 and -3 in the hypothalamus. Regulators of apoptosis such as FADD, Bcl-2, Bcl-xL and p53 were also increased, whereas p-IκB and c-FLIPL were decreased. This was accompanied by increased levels of Nox-4 and catalase, enzymes involved in oxidative stress. In summary, the hypothalamus of diabetic IRS2(-/-) mice showed an increase in oxidative stress and inflammatory markers that finally resulted in cell death via substantial activation of the extrinsic apoptotic pathway. Conversely, non-diabetic IRS2(-/-) mice did not show cell death in the hypothalamus, possibly owing to an increase in the levels of circulating IGF-I and in the enhanced hypothalamic IGF-IR phosphorylation that would lead to the stimulation of survival pathways. In conclusion, diabetes in IRS2-deficient male mice is associated with increased oxidative stress and apoptosis in the hypothalamus. © 2016. Published by The Company of Biologists Ltd.

  8. Potency of full-length MGF to induce maximal activation of the IGF-I R Is similar to recombinant human IGF-I at high equimolar concentrations

    NARCIS (Netherlands)

    J.A.M.J.L. Janssen (Joseph); L.J. Hofland (Leo); C.J. Strasburger; E.S.R.D. Van Dungen (Elisabeth S.R. Den); M. Thevis (Mario)

    2016-01-01

    textabstractAims To compare full-length mechano growth factor (full-length MGF) with human recombinant insulin-like growth factor-I (IGF-I) and human recombinant insulin (HI) in their ability to activate the human IGF-I receptor (IGF-IR), the human insulin receptor (IR-A) and the human insulin

  9. Insulin and the insulin-like growth factors I and II are mitogenic to cultured rat sciatic nerve segments and stimulate [3H]thymidine incorporation through their respective receptors

    DEFF Research Database (Denmark)

    Svenningsen, Åsa Fex; Kanje, M

    1996-01-01

    , on [3H]thymidine incorporation into cultured nerve segments from the rat sciatic nerve. Segments cultured in nM (0.1-1.7 nM) concentrations of insulin, truncated IGF-I (tIGF-I), long R3IGF-I, or IGF-II exhibited an increase in [3H]thymidine incorporation compared with control segments. IGF-II was most...... potent. JB1, an IGF-I antagonist, counteracted the effects of tIGF-I and insulin. The results suggest that non-neuronal cells in the nerve segment, probably Schwann cells, possess distinct receptors for insulin, IGF-I, and IGF-II and that these receptors may be involved in the control of Schwann cell...

  10. 20 kDa human growth hormone (20K hGH) stimulates insulin-like growth factor-I (IGF-I) gene expression at lower concentrations than 22K hGH in hGH receptor-expressing Ba/F3 cells.

    Science.gov (United States)

    Yoshizato, H; Tanaka, M; Fujikawa, T; Higashimoto, Y; Shimizu, A; Nakashima, K

    2000-03-01

    Growth hormone (GH) secreted from the pituitary is essential for postnatal growth in animals. GH exerts its actions by a direct effect on target organs and by stimulating insulin-like growth factor I (IGF-I) production. In the human pituitary, there is a naturally occurring variant protein which has a molecular mass of 20 kDa (20K hGH) besides the major 22 kDa hGH (22K hGH), but the physiological actions of 20K hGH are still poorly understood. In this study we have examined its effects on the IGF-I mRNA expression in the pro B-cell line Ba/F3 cells stably expressing hGH receptor (Ba/F3-hGHR). Ba/F3-hGHR cells were incubated for 2 h with a series of various concentrations (10 pM to approximately 10 nM) of 20K or 22K hGH. The IGF-I mRNA expression in the Ba/F3-hGHR cells was detected by the RT-PCR method. IGF-I gene expression was increased by 20K and 22K hGH stimulation, but not by PRL or IL-3 in the Ba/F3-hGHR. And this effect was not observed in parental Ba/F3 cells. Lower concentrations of 20K hGH more strongly induced IGF-I gene expression than 22K-hGH. These results suggest that 20K and 22K hGH stimulate the IGF-I gene expression in the Ba/F3-hGHR through hGH receptors, and that the stronger effect of 20K hGH than that of 22K hGH in enhancing the IGF-I gene expression may be correlated with a 20K hGH specific receptor dimerization mechanism.

  11. Metformin-mediated growth inhibition involves suppression of the IGF-I receptor signalling pathway in human pancreatic cancer cells

    International Nuclear Information System (INIS)

    Karnevi, Emelie; Said, Katarzyna; Andersson, Roland; Rosendahl, Ann H

    2013-01-01

    Epidemiological studies have shown direct associations between type 2 diabetes and obesity, both conditions associated with hyperglycaemia and hyperinsulinemia, and the risk of pancreatic cancer. Up to 80% of pancreatic cancer patients present with either new-onset type 2 diabetes or impaired glucose tolerance at the time of diagnosis. Recent population studies indicate that the incidence of pancreatic cancer is reduced among diabetics taking metformin. In this study, the effects of exposure of pancreatic cancer cells to high glucose levels on their growth and response to metformin were investigated. The human pancreatic cancer cell lines AsPC-1, BxPC-3, PANC-1 and MIAPaCa-2 were grown in normal (5 mM) or high (25 mM) glucose conditions, with or without metformin. The influence by metformin on proliferation, apoptosis and the AMPK and IGF-IR signalling pathways were evaluated in vitro. Metformin significantly reduced the proliferation of pancreatic cancer cells under normal glucose conditions. Hyperglycaemia however, protected against the metformin-induced growth inhibition. The anti-proliferative actions of metformin were associated with an activation of AMP-activated protein kinase AMPK Thr172 together with an inhibition of the insulin/insulin-like growth factor-I (IGF-I) receptor activation and downstream signalling mediators IRS-1 and phosphorylated Akt. Furthermore, exposure to metformin during normal glucose conditions led to increased apoptosis as measured by poly(ADP-ribose) polymerase (PARP) cleavage. In contrast, exposure to high glucose levels promoted a more robust IGF-I response and Akt activation which correlated to stimulated AMPK Ser485 phosphorylation and impaired AMPK Thr172 phosphorylation, resulting in reduced anti-proliferative and apoptotic effects by metformin. Our results indicate that metformin has direct anti-tumour activities in pancreatic cancer cells involving AMPK Thr172 activation and suppression of the insulin/IGF signalling pathways

  12. Genetic, molecular and functional analyses of complement factor I deficiency

    DEFF Research Database (Denmark)

    Nilsson, S.C.; Trouw, L.A.; Renault, N.

    2009-01-01

    Complete deficiency of complement inhibitor factor I (FI) results in secondary complement deficiency due to uncontrolled spontaneous alternative pathway activation leading to susceptibility to infections. Current genetic examination of two patients with near complete FI deficiency and three patie...

  13. The pivotal role of insulin-like growth factor I in normal mammary development.

    Science.gov (United States)

    Kleinberg, David L; Barcellos-Hoff, Mary Helen

    2011-09-01

    Mammary development begins in puberty in response to an estrogen (E(2)) surge. E(2) does not act alone. It relies on pituitary growth hormone (GH) to induce insulin-like growth factor I (IGF-I) production in the mammary stromal compartment. In turn, IGF-I permits E(2) (and progesterone) action. During puberty, E(2) and IGF-I synergize for ductal morphogenesis. During pregnancy, progesterone joins IGF-I and E(2) to stimulate secretory differentiation necessary to produce milk. Prolactin stimulates milk production, while transforming growth factor-β inhibits proliferation. The orchestrated action of hormones, growth factors, and receptors necessary for mammary development and function are also critical in breast cancer. Copyright © 2011. Published by Elsevier Inc.

  14. Studies on binding and mitogenic effect of insulin and insulin-like growth factor I in glomerular mesangial cells

    International Nuclear Information System (INIS)

    Conti, F.G.; Striker, L.J.; Lesniak, M.A.; MacKay, K.; Roth, J.; Striker, G.E.

    1988-01-01

    The mesangial cells are actively involved in regulating glomerular hemodynamics. Their overlying endothelium is fenestrated; therefore, these cells are directly exposed to plasma substances, including hormones such as insulin and insulin-like growth factor I (IGF-I). These peptides may contribute to the mesangial sclerosis and cellular hyperplasia that characterize diabetic glomerulopathy. We report herein the characterization of the receptors and the mitogenic effects of IGF-I and insulin on mouse glomerular mesangial cells in culture. The IGF-I receptor was characterized on intact cells. The Kd of the IGF-I receptor was 1.47 X 10(-9) M, and the estimated number of sites was 64,000 receptors/cell. The binding was time, temperature, and pH dependent, and the receptor showed down-regulation after exposure to serum. The expression of the receptor did not change on cells at different densities. The specific binding for insulin was too low to allow characterization of the insulin receptor on intact cells. However, it was possible to identify the insulin receptor in a wheat germ agglutinin-purified preparation of solubilized mesangial cells. This receptor showed the characteristic features of the insulin receptor, including pH dependence of binding and a curvilinear Scatchard plot. The mitogenic effects of insulin and IGF-I on mesangial cells were measured by the incorporation of [3H]thymidine into DNA. IGF-I was more potent than insulin. The half-maximal response to IGF-I stimulation occurred at 1.3 X 10(-10) M, and a similar increase with insulin was observed at concentrations in the range of 10(-7) M, suggesting that this insulin action was mediated through the IGF-I receptor. These data show that the mouse microvascular smooth muscle cells of the glomerulus express a cell surface receptor for IGF-I in vitro and that this peptide is a potent mitogen for these mesangial cells

  15. receptores

    Directory of Open Access Journals (Sweden)

    Salete Regina Daronco Benetti

    2006-01-01

    Full Text Available Se trata de un estudio etnográfico, que tuvo lo objetivo de interpretar el sistema de conocimiento y del significado atribuidos a la sangre referente a la transfusión sanguínea por los donadores y receptores de un banco de sangre. Para la colecta de las informaciones se observaron los participantes y la entrevista etnográfica se realizó el análisis de dominio, taxonómicos y temáticos. Los dominios culturales fueron: la sangre es vida: fuente de vida y alimento valioso; creencias religiosas: fuentes simbólicas de apoyos; donación sanguínea: un gesto colaborador que exige cuidarse, gratifica y trae felicidad; donación sanguínea: fuente simbólica de inseguridad; estar enfermo es una condición para realizar transfusión sanguínea; transfusión sanguínea: esperanza de vida; Creencias populares: transfusión sanguínea como riesgo para la salud; donadores de sangre: personas benditas; donar y recibir sangre: como significado de felicidad. Temática: “líquido precioso que origina, sostiene, modifica la vida, provoca miedo e inseguridad”.

  16. Insulin-like growth factor I: a biologic maturation indicator.

    Science.gov (United States)

    Ishaq, Ramy Abdul Rahman; Soliman, Sanaa Abou Zeid; Foda, Manal Yehya; Fayed, Mona Mohamed Salah

    2012-11-01

    Determination of the maturation level and the subsequent evaluation of growth potential during preadolescence and adolescence are important for optimal orthodontic treatment planning and timing. This study was undertaken to evaluate the applicability of insulin-like growth factor I (IGF-I) blood level as a maturation indicator by correlating it to the cervical vertebral maturation index. The study was conducted with 120 subjects, equally divided into 60 males (ages, 10-18 years) and 60 females (ages, 8-16 years). A lateral cephalometric radiograph and a blood sample were taken from each subject. For each subject, cervical vertebral maturation and IGF-I serum level were assessed. Mean values of IGF-I in each stage of cervical vertebral maturation were calculated, and the means in each stage were statistically compared with those of the other stages. The IGF-I mean value at each cervical vertebral maturation stage was statistically different from the mean values at the other stages. The highest mean values were observed in stage 4, followed by stage 5 in males and stage 3 in females. IGF-I serum level is a reliable maturation indicator that could be applied in orthodontic diagnosis. Copyright © 2012 American Association of Orthodontists. Published by Mosby, Inc. All rights reserved.

  17. Insulin-like growth factor I/somatomedin C: a potent inducer of oligodendrocyte development

    International Nuclear Information System (INIS)

    McMorris, F.A.; Smith, T.M.; DeSalvo, S.; Furlanetto, R.W.

    1986-01-01

    Cell cultures established from cerebrum of 1-day-old rats were used to investigate hormonal regulation of the development of oligodendrocytes, which synthesize myelin in the central nervous system. The number of oligodendrocytes that developed was preferentially increased by insulin, or by insulin-like growth factor I (IGF-I), also known as somatomedin C. High concentrations of insulin were required for substantial induction of oligodendrocyte development, whereas only 3.3 ng of IGF-I per ml was needed for a 2-fold increase in oligodendrocyte numbers. At an IGF-I concentration of 100 ng/ml, oligodendrocyte numbers were increased 6-fold in cultures grown in the presence of 10% fetal bovine serum, or up to 60-fold in cultures maintained in serum-free medium. IGF-I produced less than a 2-fold increase in the number of nonoligodendroglial cells in the same cultures. Type I IGF receptors were identified on oligodendrocytes and on a putative oligodendrocyte precursor cell population identified by using mouse monoclonal antibody A2B5. Radioligand binding assays were done. These results indicate that IGF-I is a potent inducer of oligodendrocyte development and suggest a possible mechanism based on IGF deficiency for the hypomyelination that results from early postnatal malnutrition

  18. The Role of Insulin Receptor Isoforms in Diabetes and Its Metabolic and Vascular Complications

    Directory of Open Access Journals (Sweden)

    O. Escribano

    2017-01-01

    Full Text Available The insulin receptor (IR presents by alternative splicing two isoforms: IRA and IRB. The differential physiological and pathological role of both isoforms is not completely known, and it is determinant the different binding affinity for insulin-like growth factor. IRB is more abundant in adult tissues and it exerts mainly the metabolic actions of insulin, whereas IRA is mainly expressed in fetal and prenatal period and exerts mitogenic actions. However, the change in the expression profile of both IR isoforms and its dysregulation are associated with the development of different pathologies, such as cancer, insulin resistance, diabetes, obesity, and atherosclerosis. In some of them, there is a significant increase of IRA/IRB ratio conferring a proliferative and migratory advantage to different cell types and favouring IGF-II actions with a sustained detriment in the metabolic effects of insulin. This review discussed specifically the role of IR isoforms as well as IGF-IR in diabetes and its associated complications as obesity and atherosclerosis. Future research with new IR modulators might be considered as possible targets to improve the treatment of diabetes and its associated complications.

  19. Insulin and insulin-like growth factor I exert different effects on plasminogen activator production or cell growth in the ovine thyroid cell line OVNIS.

    Science.gov (United States)

    Degryse, B; Maisonobe, F; Hovsépian, S; Fayet, G

    1991-11-01

    Insulin and Insulin-like Growth Factor I (IGF-I) are evaluated for their capacity to affect cell proliferation and plasminogen activator (PA) activity production in an ovine thyroid cell line OVNIS. Insulin at physiological and supraphysiological doses induces cell proliferation and increases PA activity. IGF-I, which is also clearly mitogenic for these cells, surprisingly does not modulate PA activity. The results indicate that the growth promoting effect is mediated through the insulin and IGF-I receptors whereas PA activity is solely regulated via the insulin receptors.

  20. A Concerted Action Of Estradiol And Insulin Like Growth Factor I Underlies Sex Differences In Mood Regulation By Exercise.

    Science.gov (United States)

    Munive, Victor; Santi, Andrea; Torres-Aleman, Ignacio

    2016-05-12

    Mood homeostasis present sexually dimorphic traits which may explain sex differences in the incidence of mood disorders. We explored whether diverse behavioral-setting components of mood may be differentially regulated in males and females by exercise, a known modulator of mood. We found that exercise decreases anxiety only in males. Conversely, exercise enhanced resilience to stress and physical arousal, two other important components of mood, only in females. Because exercise increases brain input of circulating insulin-like growth factor I (IGF-I), a potent modulator of mood, we explored whether sex-specific actions of exercise on mood homeostasis relate to changes in brain IGF-I input. We found that exercise increased hippocampal IGF-I levels only in cycling females. Underlying mechanism involved activation of estrogen (E2) receptors in brain vessels that led to increased uptake of serum IGF-I as E2 was found to stimulate IGF-I uptake in brain endothelial cells. Indeed, modulatory effects of exercise on mood were absent in female mice with low serum IGF-I levels or after either ovariectomy or administration of an E2 receptor antagonist. These results suggest that sex-specific brain IGF-I responses to physiological stimuli such as exercise contribute to dimorphic mood homeostasis that may explain sex differences in affective disorders.

  1. Insulin-like growth factor-I in growth and metabolism

    DEFF Research Database (Denmark)

    Backeljauw, P; Bang, P; Dunger, D B

    2010-01-01

    Deficiency of insulin-like growth factor-I (IGF-I) results in growth failure. A variety of molecular defects have been found to underlie severe primary IGF-I deficiency (IGFD), in which serum IGF-I concentrations are substantially decreased and fail to respond to GH therapy. Identification of mor...

  2. Serum insulin-like growth factor-I and body composition in community dwelling older people

    NARCIS (Netherlands)

    Jakobsdottir, S.; van Nieuwpoort, I.C.; Schaap, L.A.; van Schoor, N.M.; Lips, P.T.A.M.; Drent, M.L.

    2010-01-01

    Objectives The decline in the growth hormoneinsulin-like growth factor-I (GHIGF-I) axis during normal aging might be involved in the changes in body composition associated with increasing age. We conducted a study to investigate serum IGF-I levels across different age categories and a possible

  3. Detection of polymorphism of the insulin-like growth factor-I (IGF-I ...

    African Journals Online (AJOL)

    Molecular genetic selection on individual genes is a promising method to genetically improve economically important traits in chickens. The insulin-like growth factor-I (IGF-I) gene may play important roles in growth of multiple tissues, including muscle cells, cartilage and bone. In the present study, polymorphism of the ...

  4. Growth hormone-insuline-like growth factor-I system in pejerrey Odontesthes bonariensis (Atheriniformes

    Directory of Open Access Journals (Sweden)

    S.E. Arranz

    2008-07-01

    Full Text Available Using biotechnology to increase the growth rates of fish is likely to reduce production costs per unit of food. Among vertebrates, fish appear to occupy a unique position, when growth patterns are considered. With few exceptions, fish species tend to grow indeterminately, implying that size is never fixed. Both hyperplasia and hypertrophy contribute to post-larval muscle growth in fish. Growth hormone (GH - Insulin-like Growth Factor I (IGF-I is the most important growth axis in fish. Our experimental model, the pejerrey, Odontesthes bonariensis (Ateriniformes is a South American inland water fish considered to be a promising species for intensive aquaculture. However, one major drawback to achieve this goal is its slow growth in captivity. In order to understand how growth is regulated in this species, our first objective was to characterized pejerrey GH- IGF-I axis. We first cloned and characterized pejerrey (pj GH, IGF-I and the growth hormone receptors (GHRs I and II. In addition to providing valuable data for evolutionary comparison of GH, investigation of GH action in teleosts is particularly important because of its potential application in aquaculture. GH can not only promote the somatic growth in fish but also lower dietary protein requirements. A prerequisite for providing sufficient amounts of GH for basic research and aquaculture application is a large-scale production of GH. For that purpose, recombinant pjGH was expressed in a bacterial system. Protocols for solubilization and proper folding were achieved. Activity of recombinant pjGH was assessed in fish by measuring the liver IGF-I response to different doses of GH. IGF-I transcript was measured in the liver after pjGHr in vivo stimulation by means of quantitative real-time PCR assays. A dose-dependent response of IGF-I mRNA was observed after pjGHr administration, and reached a 6 fold IGF-I maximum increase over control group when 2.5 µg pjGH /g-body weight were injected

  5. Insulin-like growth factor-I gene delivery to astrocytes reduces their inflammatory response to lipopolysaccharide

    Directory of Open Access Journals (Sweden)

    Goya Rodolfo G

    2011-03-01

    Full Text Available Abstract Background Insulin-like growth factor-I (IGF-I exerts neuroprotective actions in the central nervous system that are mediated at least in part by control of activation of astrocytes. In this study we have assessed the efficacy of exogenous IGF-I and IGF-I gene therapy in reducing the inflammatory response of astrocytes from cerebral cortex. Methods An adenoviral vector harboring the rat IGF-I gene and a control adenoviral vector harboring a hybrid gene encoding the herpes simplex virus type 1 thymidine kinase fused to Aequorea victoria enhanced green fluorescent protein were used in this study. Primary astrocytes from mice cerebral cortex were incubated for 24 h or 72 h with vehicle, IGF-I, the IGF-I adenoviral vector, or control vector; and exposed to bacterial lipopolysaccharide to induce an inflammatory response. IGF-I levels were measured by radioimmunoassay. Levels of interleukin 6, tumor necrosis factor-α, interleukin-1β and toll-like receptor 4 mRNA were assessed by quantitative real-time polymerase chain reaction. Levels of IGF-I receptor and IGF binding proteins 2 and 3 were assessed by western blotting. The subcellular distribution of nuclear factor κB (p65 was assessed by immunocytochemistry. Statistical significance was assessed by one way analysis of variance followed by the Bonferroni pot hoc test. Results IGF-I gene therapy increased IGF-I levels without affecting IGF-I receptors or IGF binding proteins. Exogenous IGF-I, and IGF-I gene therapy, decreased expression of toll-like receptor 4 and counteracted the lipopolysaccharide-induced inflammatory response of astrocytes. In addition, IGF-I gene therapy decreased lipopolysaccharide-induced translocation of nuclear factor κB (p65 to the cell nucleus. Conclusion These findings demonstrate efficacy of exogenous IGF-I and of IGF-I gene therapy in reducing the inflammatory response of astrocytes. IGF-I gene therapy may represent a new approach to reduce inflammatory

  6. Dihydrotestosterone inhibits hair growth in mice by inhibiting insulin-like growth factor-I production in dermal papillae.

    Science.gov (United States)

    Zhao, Juan; Harada, Naoaki; Okajima, Kenji

    2011-10-01

    We demonstrated that insulin-like growth factor-I (IGF-I) production in dermal papillae was increased and hair growth was promoted after sensory neuron stimulation in mice. Although the androgen metabolite dihydrotestosterone (DHT) inhibits hair growth by negatively modulating growth-regulatory effects of dermal papillae, relationship between androgen metabolism and IGF-I production in dermal papillae is not fully understood. We examined whether DHT inhibits IGF-I production by inhibiting sensory neuron stimulation, thereby preventing hair growth in mice. Effect of DHT on sensory neuron stimulation was examined using cultured dorsal root ganglion (DRG) neurons isolated from mice. DHT inhibits calcitonin gene-related peptide (CGRP) release from cultured DRG neurons. The non-steroidal androgen-receptor antagonist flutamide reversed DHT-induced inhibition of CGRP release. Dermal levels of IGF-I and IGF-I mRNA, and the number of IGF-I-positive fibroblasts around hair follicles were increased at 6h after CGRP administration. DHT administration for 3weeks decreased dermal levels of CGRP, IGF-I, and IGF-I mRNA in mice. Immunohistochemical expression of IGF-I and the number of proliferating cells in hair follicles were decreased and hair re-growth was inhibited in animals administered DHT. Co-administration of flutamide and CGRP reversed these changes induced by DHT administration. These observations suggest that DHT may decrease IGF-I production in dermal papillae by inhibiting sensory neuron stimulation through interaction with the androgen receptor, thereby inhibiting hair growth in mice. Copyright © 2011 Elsevier Ltd. All rights reserved.

  7. A bispecific enediyne-energized fusion protein targeting both epidermal growth factor receptor and insulin-like growth factor 1 receptor showing enhanced antitumor efficacy against non-small cell lung cancer.

    Science.gov (United States)

    Guo, Xiao-Fang; Zhu, Xiao-Fei; Cao, Hai-Ying; Zhong, Gen-Shen; Li, Liang; Deng, Bao-Guo; Chen, Ping; Wang, Pei-Zhen; Miao, Qing-Fang; Zhen, Yong-Su

    2017-04-18

    Epidermal growth factor receptor (EGFR) and insulin-like growth factor 1 receptor (IGF-1R) both overexpressed on non-small cell lung cancer (NSCLC) and are known cooperatively to promote tumor progression and drug resistance. This study was to construct a novel bispecific fusion protein EGF-IGF-LDP-AE consisting of EGFR and IGF-IR specific ligands (EGF and IGF-1) and lidamycin, an enediyne antibiotic with potent antitumor activity, and investigate its antitumor efficacy against NSCLC. Binding and internalization assays showed that EGF-IGF-LDP protein could bind to NSCLC cells with high affinity and then internalized into cells with higher efficiency than that of monospecific proteins. In vitro, the enediyne-energized analogue of bispecific fusion protein (EGF-IGF-LDP-AE) displayed extremely potent cytotoxicity to NSCLC cell lines with IC50protein EGF-IGF-LDP-AE was more cytotoxic than monospecific proteins (EGF-LDP-AE and LDP-IGF-AE) and lidamycin. In vivo, EGF-IGF-LDP-AE markedly inhibited the growth of A549 xenografts, and the efficacy was more potent than that of lidamycin and monospecific counterparts. EGF-IGF-LDP-AE caused significant cell cycle arrest and it also induced cell apoptosis in a dosage-dependent manner. Pretreatment with EGF-IGF-LDP-AE inhibited EGF-, IGF-stimulated EGFR and IGF-1R phosphorylation, and blocked two main downstream signaling molecules AKT and ERK activation. These data suggested that EGF-LDP-IGF-AE protein would be a promising targeted agent for NSCLC patients with EGFR and/or IGF-1R overexpression.

  8. The neuroprotective effects of intramuscular insulin-like growth factor-I treatment in brain ischemic rats.

    Directory of Open Access Journals (Sweden)

    Heng-Chih Chang

    Full Text Available Brain ischemia leads to muscle inactivity-induced atrophy and may exacerbate motor function deficits. Intramuscular insulin-like growth factor I (IGF-I injection has been shown to alleviate the brain ischemia-induced muscle atrophy and thus improve the motor function. Motor function is normally gauged by the integrity and coordination of the central nervous system and peripheral muscles. Whether brain ischemic regions are adaptively changed by the intramuscular IGF-I injection is not well understood. In this study, the effect of intramuscular IGF-I injection was examined on the central nervous system of brain ischemic rats. Rats were divided into 4 groups: sham control, brain ischemia control, brain ischemia with IGF-I treatment, and brain ischemia with IGF-I plus IGF-I receptor inhibitor treatment. Brain ischemia was induced by right middle cerebral artery occlusion. IGF-I and an IGF-1 receptor inhibitor were injected into the affected calf and anterior tibialis muscles of the treated rats for 4 times. There was an interval of 2 days between each injection. Motor function was examined and measured at the 24 hours and 7 days following a brain ischemia. The affected hind-limb muscles, sciatic nerve, lumbar spinal cord, and motor cortex were collected for examination after euthanizing the rats. IGF-I expression in the central nervous system and affected muscles were significantly decreased after brain ischemia. Intramuscular IGF-I injection increased the IGF-I expression in the affected muscles, sciatic nerve, lumbar spinal cord, and motor cortex. It also increased the p-Akt expression in the affected motor cortex. Furthermore, intramuscular IGF-I injection decreased the neuronal apoptosis and improved the motor function. However, co-administration of the IGF-I receptor inhibitor eliminated these effects. Intramuscular IGF-I injection after brain ischemia attenuated or reversed the decrease of IGF-I in both central and peripheral tissues, and

  9. Cytokines and soluble tumour necrosis factor I receptor levels during pretransplant conditioning in allogeneic stem-cell transplantation

    DEFF Research Database (Denmark)

    Andersen, Johnny; Heilmann, Carsten; Jacobsen, Niels

    2005-01-01

    The inflammatory response induced by the conditioning regime may be related to the outcome in allogeneic stem-cell transplantation (SCT). However, previous statements concerning the prognostic significance of cytokine measurements during conditioning have not been conclusive. We investigated...... a broad range of cytokines in plasma samples drawn daily immediately before start of pretransplant conditioning and during the conditioning. The presented data indicate that single-day measurements of inflammatory cytokines during conditioning may lead to unreliable conclusions concerning their prognostic...

  10. Novel CFI mutation in a patient with leukocytoclastic vasculitis may redefine the clinical spectrum of Complement Factor I deficiency

    DEFF Research Database (Denmark)

    Bay, Jakob Thaning; Katzenstein, Terese Lea; Kofoed, Kristian

    2015-01-01

    presentation of Factor I deficiency varies and includes severe recurrent bacterial infections, glomerulonephritis and autoimmune diseases. The patient, a 28-years old woman with consanguineous parents, presented with recurrent leukocytoclastic vasculitis in the lower extremities with no associated systemic...... mutations vary among patients sole association with leukocytoclastic vasculitis redefines the clinical spectrum of complete Factor I deficiency....

  11. Localization and quantification of binding sites for follicle-stimulating hormone, luteinizing hormone, growth hormone, and insulin-like growth factor I in sheep ovarian follicles.

    Science.gov (United States)

    Eckery, D C; Moeller, C L; Nett, T M; Sawyer, H R

    1997-09-01

    In sheep, growth and development of ovarian follicles beyond 2 mm in diameter is acutely dependent on gonadotropin support. As a consequence, following hypophysectomy (HPX) or hypothalamic-pituitary stalk disconnection (HPD), growth of follicles beyond 2 mm is arrested and all follicles > 2 mm undergo atresia. Although administration of exogenous gonadotropins stimulates follicular growth and ovulation in HPD ewes, follicles in HPX ewes remain unresponsive unless growth hormone (GH) is also given. To determine whether the difference in follicular sensitivity to gonadotropins after HPD (gonadotropin sensitive) or HPX (gonadotropin insensitive) is related to the distribution and quantity of binding sites for FSH, LH, and/or insulin-like growth factor I (IGF-I), binding sites for these hormones were localized and quantified using topical autoradiography in healthy follicles from control (pituitary-intact), HPD, and HPX ewes. In addition, in situ hybridization was performed to localize mRNA for GH and FSH receptors. Irrespective of treatment, binding of FSH and mRNA for FSH receptor were greatest (p membrana granulosa; LH binding was greatest (p receptor was most abundant (p membrana granulosa and oocytes of small antral and preantral follicles. Compared to levels in controls and HPD ewes, the level of GH receptor mRNA was lower (p receptors for FSH, LH, or IGF-I. The observed reduction of mRNA for GH receptor in the membrana granulosa of follicles from HPX ewes provides evidence that GH may play an important role in early stages of folliculogenesis and that it is involved in the maintenance of sensitivity to gonadotropins.

  12. Expression, content, and localization of insulin-like growth factor I in human achilles tendon

    DEFF Research Database (Denmark)

    Olesen, Jens L; Heinemeier, Katja M; Langberg, Henning

    2006-01-01

    In animals insulin-like growth factor I (IGF-I) stimulates collagen production by fibroblasts and is expressed in tendons together with its binding protein 4 (IGFBP-4). However, the presence of IGF-I and IGFBP-4 in human tendon tissue is not described. Tissue IGF-I content was examined by immunof...... the tendon fibroblasts and that mRNA for IGF-I and IGFBP-4 can be determined in human tendon tissue. The present study adds support for the roles of IGF-I and IGFBP-4 in the regulation of tendon adaptive responses to mechanical loading....

  13. Insulin-like growth factor-I in growth and metabolism

    DEFF Research Database (Denmark)

    Backeljauw, P; Bang, P; Dunger, D B

    2010-01-01

    Deficiency of insulin-like growth factor-I (IGF-I) results in growth failure. A variety of molecular defects have been found to underlie severe primary IGF-I deficiency (IGFD), in which serum IGF-I concentrations are substantially decreased and fail to respond to GH therapy. Identification of more...... patients with primary or secondary IGFD is likely with investigative and diagnostic progress, particularly in the assessment of children with idiopathic short stature. Diagnosis of IGFD requires accurate and reliable IGF-I assays, adequate normative data for reference, and knowledge of IGF-I physiology...

  14. Insulin-like growth factors I and II in healthy women with and without established osteoporosis

    DEFF Research Database (Denmark)

    Ravn, Pernille; Spencer, E M; Christiansen, C

    1995-01-01

    .05) was seen in the nandrolone decanoate-treated group. The same tendency was seen for hormone replacement therapy, although it was not significant. In conclusion, the serum level of IGF-I is high in young women, when peak bone mass is attained, and low in postmenopausal women with established osteoporosis.......We measured serum concentrations of insulin-like growth factors I and II (IGF-I and IGF-II) by radioimmunoassay in 107 healthy women aged 28-78 years and in 116 women with established osteoporosis. The women with established osteoporosis were randomized to a 1-year double-blind, placebo...

  15. Skeletal unloading causes resistance of osteoprogenitor cells to parathyroid hormone and to insulin-like growth factor-I

    Science.gov (United States)

    Kostenuik, P. J.; Harris, J.; Halloran, B. P.; Turner, R. T.; Morey-Holton, E. R.; Bikle, D. D.

    1999-01-01

    Skeletal unloading decreases bone formation and osteoblast number in vivo and decreases the number and proliferation of bone marrow osteoprogenitor (BMOp) cells in vitro. We tested the ability of parathyroid hormone (PTH) to stimulate BMOp cells in vivo by treating Sprague Dawley rats (n = 32) with intermittent PTH(1-34) (1 h/day at 8 microg/100 g of body weight), or with vehicle via osmotic minipumps during 7 days of normal weight bearing or hind limb unloading. Marrow cells were flushed from the femur and cultured at the same initial density for up to 21 days. PTH treatment of normally loaded rats caused a 2.5-fold increase in the number of BMOp cells, with similar increases in alkaline phosphatase (ALP) activity and mineralization, compared with cultures from vehicle-treated rats. PTH treatment of hind limb unloaded rats failed to stimulate BMOp cell number, ALP activity, or mineralization. Hind limb unloading had no significant effect on PTH receptor mRNA or protein levels in the tibia. Direct in vitro PTH challenge of BMOp cells isolated from normally loaded bone failed to stimulate their proliferation and inhibited their differentiation, suggesting that the in vivo anabolic effect of intermittent PTH on BMOp cells was mediated indirectly by a PTH-induced factor. We hypothesize that this factor is insulin-like growth factor-I (IGF-I), which stimulated the in vitro proliferation and differentiation of BMOp cells isolated from normally loaded bone, but not from unloaded bone. These results suggest that IGF-I mediates the ability of PTH to stimulate BMOp cell proliferation in normally loaded bone, and that BMOp cells in unloaded bone are resistant to the anabolic effect of intermittent PTH therapy due to their resistance to IGF-I.

  16. Recombinant gilthead seabream (Sparus aurata) insulin-like growth factor-I: subcloning, expression in Escherichia coli, purification and characterization.

    Science.gov (United States)

    Fine, M; Amuly, R; Sandowski, Y; Marchant, T A; Chan, S J; Gertler, A; Funkenstein, B

    1997-04-01

    Gilthead seabream (Sparus aurata) insulin-like growth factor-I (gsIGF-I) cDNA coding for the mature protein was cloned in a pGEM-3Z vector, and then transferred into prokaryotic expression vector pET-11a and expressed in Escherichia coli BL21(DE3) cells upon induction with isopropyl thiogalactoside. The expressed protein contained within the inclusion-body pellet was solubilized in 4.5 M urea, refolded for 24 h at pH 11.3 in the presence of catalytic amounts of cysteine and purified to over 98% purity, as a monomeric methionyl-gsIGF-I. Amino acid composition and N-terminal sequence confirmed the identity to be the predicted protein. Binding assays of the 125I-gsIGF-I to gilthead seabream or carp (Cyprinus carpio) sera resulted in high specific binding, indicating the existence of one or more IGF-binding proteins. In binding experiments to crude gilthead seabream brain homogenate, using human (h) IGF-I as a ligand, the respective IC50 value of hIGF-I was about fourfold lower than that of gsIGF-I. Recombinant gsIGF-I exhibited mitogenic activity in a mouse mammary gland-derived MME-L1 cell line which was approximately 200-fold lower than that of hIGF-1. Binding experiments to intact MME-L1 cells suggests that this difference most likely results from a correspondingly lower affinity for IGF-I receptor in these cells. In contrast, the activities of gsIGF-I and hIGF-I measured by 35S uptake by gill arches from the goldfish (Carassius auratus) were identical, indicating that the recombinant gsIGF-I is biologically active.

  17. The insulin-like growth factor I system: physiological and pathophysiological implication in cardiovascular diseases associated with metabolic syndrome.

    Science.gov (United States)

    Ren, Jun; Anversa, Piero

    2015-02-15

    Metabolic syndrome is a cluster of risk factors including obesity, dyslipidemia, hypertension, and insulin resistance. A number of theories have been speculated for the pathogenesis of metabolic syndrome including impaired glucose and lipid metabolism, lipotoxicity, oxidative stress, interrupted neurohormonal regulation and compromised intracellular Ca(2+) handling. Recent evidence has revealed that adults with severe growth hormone (GH) and insulin-like growth factor I (IGF-1) deficiency such as Laron syndrome display increased risk of stroke and cardiovascular diseases. IGF-1 signaling may regulate contractility, metabolism, hypertrophy, apoptosis, autophagy, stem cell regeneration and senescence in the heart to maintain cardiac homeostasis. An inverse relationship between plasma IGF-1 levels and prevalence of metabolic syndrome as well as associated cardiovascular complications has been identified, suggesting the clinical promises of IGF-1 analogues or IGF-1 receptor activation in the management of metabolic and cardiovascular diseases. However, the underlying pathophysiological mechanisms between IGF-1 and metabolic syndrome are still poorly understood. This mini-review will discuss the role of IGF-1 signaling cascade in the prevalence of metabolic syndrome in particular the susceptibility to overnutrition and sedentary life style-induced obesity, dyslipidemia, insulin resistance and other features of metabolic syndrome. Special attention will be dedicated in IGF-1-associated changes in cardiac responses in various metabolic syndrome components such as insulin resistance, obesity, hypertension and dyslipidemia. The potential risk of IGF-1 and IGF-1R stimulation such as tumorigenesis is discussed. Therapeutic promises of IGF-1 and IGF-1 analogues including mecasermin, mecasermin rinfabate and PEGylated IGF-1 will be discussed. Copyright © 2014 Elsevier Inc. All rights reserved.

  18. Trastuzumab regulates IGFBP-2 and IGFBP-3 to mediate growth inhibition: implications for the development of predictive biomarkers for trastuzumab resistance.

    Science.gov (United States)

    Dokmanovic, Milos; Shen, Yi; Bonacci, Tabetha M; Hirsch, Dianne S; Wu, Wen Jin

    2011-06-01

    Activation of insulin-like growth factor-I receptor (IGF-IR) signaling is an important mechanism for trastuzumab resistance. IGF-binding proteins (IGFBP) modulate IGF-IR signaling and play important roles in the control of breast cancer progression. In this article, we report that trastuzumab treatment enhances the expression and secretion of IGFBP-3 in SKBR3 cells, a trastuzumab-sensitive breast cancer cell line, and that this upregulation of IGFBP-3 induced by trastuzumab correlates with trastuzumab-mediated growth inhibition. We describe a new role for IGFBP-3 in the regulation of IGF-I-mediated cross-talk between IGF-IR and ErbB2 signaling pathways. In particular, treatment of SKBR3 cells with recombinant IGFBP-3 blocks IGF-I-induced activation of IGF-IR and ErbB2, and stable expression of IGFBP-3 inhibits SKBR3 cell growth. We find an inverse relationship in the levels of secreted IGFBP-3 such that high levels of IGFBP-3 are associated with trastuzumab-sensitive breast cancer cells (SKBR3 and BT-474), whereas low levels of IGFBP-3 are found in trastuzumab-resistant cells (clone 3 and JIMT-1). In contrast to IGFBP-3, the secretion and expression of IGFBP-2 are upregulated in trastuzumab-resistant SKBR3 cells. Furthermore, we show that IGFBP-2 stimulates activation of ErbB2 and that trastuzumab reduces IGFBP-2-stimulated ErbB2 activation. Based on our data, we propose a novel mechanism of action whereby trastuzumab enhances the expression and secretion of IGFBP-3, which interferes with IGF-I-mediated mitogenic signaling via autocrine and paracrine mechanisms and reduces IGFBP-2-induced ErbB2 activation to mediate growth inhibition. Changes in secretion profiles of IGFBP-2 and IGFBP-3 in trastuzumab-sensitive and trastuzumab-resistant cells may promote the development of IGFBP-2 and IGFBP-3 as predictive biomarkers for trastuzumab resistance.

  19. Diminished concentrations of insulin-like growth factor I in cystic fibrosis

    DEFF Research Database (Denmark)

    Laursen, Erik; Juul, A; Lanng, S

    1995-01-01

    Cystic fibrosis is frequently accompanied by a catabolic condition with low body mass index caused by a number of disease complications. Insulin-like growth factor-I (IGF-I) is an anabolic hormone and an important marker of nutritional status, liver function, and linear growth. Available data...... on IGF-I in cystic fibrosis are sparse and conflicting. From 1990-3, 235 of our 240 patients (114 males, 121 females, median age 16.2 years, ranged 0.1-44.0 years) had IGF-I measured once by radioimmunoassay. IGF-I was significantly reduced compared with a healthy Scandinavian control population: mean...... = 0.28, p cystic fibrosis and play a part in their abnormal growth pattern....

  20. Insulin-like growth factors I and II in healthy women with and without established osteoporosis

    DEFF Research Database (Denmark)

    Ravn, Pernille; Spencer, E M; Christiansen, C

    1995-01-01

    We measured serum concentrations of insulin-like growth factors I and II (IGF-I and IGF-II) by radioimmunoassay in 107 healthy women aged 28-78 years and in 116 women with established osteoporosis. The women with established osteoporosis were randomized to a 1-year double-blind, placebo...... no correlation between IGF-I and age (r = 0.02). Correspondingly, we found no significant changes in serum IGF-I in 10 women, who were followed with serial measurements of IGFs every 3 months from 2 years before to 1 year after menopause; IGF-II revealed no correlation with age (r = 0.04). In the group of 116...... women with established osteoporosis, IGF-I was 30% lower (p

  1. Enhanced insulin-like growth factor I gene expression in regenerating rat pancreas

    International Nuclear Information System (INIS)

    Smith, F.E.; Rosen, K.M.; Villa-Komaroff, L.; Weir, G.C.; Bonner-Weir, S.

    1991-01-01

    Insulin-like growth factor I (IGF-I) mRNA expression was studied after 90% partial pancreatectomy in the rat to determine whether IGF-I was associated with pancreatic regeneration. The level of IGF-I mRNA was maximally increased (4-fold above control value) 3 days after pancreatectomy, but thereafter gradually decreased, returning to control levels by 14 days after surgery. By in situ hybridization, IGF-I mRNA in both pancreatectomized and sham-operated rats was localized to capillary endothelial cells, indicating that this is the site of IGF-I expression in the normal rat pancreas. However, enhanced IGF-I mRNA expression was localized to focal areas of regeneration unique to pancreatectomized rats. In these areas, epithelial cells of proliferating ductules and individual connective tissue cells expressed IGF-I, suggesting that IGF-I may play an important role in the growth or differentiation of pancreatic tissue

  2. Enhanced insulin-like growth factor I gene expression in regenerating rat pancreas

    Energy Technology Data Exchange (ETDEWEB)

    Smith, F.E.; Rosen, K.M.; Villa-Komaroff, L.; Weir, G.C.; Bonner-Weir, S. (E. P. Joslin Research Laboratory, Joslin Diabetes Center, Harvard Medical School, Boston, MA (USA))

    1991-07-15

    Insulin-like growth factor I (IGF-I) mRNA expression was studied after 90% partial pancreatectomy in the rat to determine whether IGF-I was associated with pancreatic regeneration. The level of IGF-I mRNA was maximally increased (4-fold above control value) 3 days after pancreatectomy, but thereafter gradually decreased, returning to control levels by 14 days after surgery. By in situ hybridization, IGF-I mRNA in both pancreatectomized and sham-operated rats was localized to capillary endothelial cells, indicating that this is the site of IGF-I expression in the normal rat pancreas. However, enhanced IGF-I mRNA expression was localized to focal areas of regeneration unique to pancreatectomized rats. In these areas, epithelial cells of proliferating ductules and individual connective tissue cells expressed IGF-I, suggesting that IGF-I may play an important role in the growth or differentiation of pancreatic tissue.

  3. Specific immunoradiometric assay of insulin-like growth factor I with use of monoclonal antibodies

    Energy Technology Data Exchange (ETDEWEB)

    Scott, M.G.; Cuca, G.C.; Petersen, J.R.; Lyle, L.R.; Burleigh, B.D.; Daughaday, W.H.

    1987-11-01

    We identified two monoclonal antibodies that bind spatially distinct epitopes on insulin-like growth factor I (IGF-I). Using these two antibodies, we developed a simultaneous, two-site immunoradiometric assay (IRMA) specific for IGF-I. This IRMA has no detectable cross reactivity with insulin, proinsulin, prolactin, or somatotropin, and less than 2% crossreactivity with IGF-II. The assay response varies linearly with IGF-I concentrations of 0-800 micrograms/L in serum; the detection limit is about 10 micrograms/L. A comparison of 26 IGF-I serum values from the IRMA and from a previously reported IGF-I specific RIA gave a correlation coefficient of 0.96 with no substantial bias (slope = 1.10). IGF-I values for serum, as an aid in assessing growth abnormalities, are easily (only three pipetting steps) obtained in less than 4 h.

  4. Application of insulin-like growth factor-I and insulin release test in diabetes mellitus

    International Nuclear Information System (INIS)

    Chen Dong; Ma Yongxiu; Duan Wenruo

    2003-01-01

    The purpose of this study was to determine the role of insulin-like growth factor-I (IGF-I) and insulin release test (IRT) in understanding the extent of damage to ability of reducing blood sugar in different types of diabetes mellitus (DM) and in selection of treatment plan and adjustment of using drugs. OGTT, IRT and determination of IGF-I level of 67 normal subjects and 217 DM patients were performed. The result was analyzed comparatively. The level of IGF-I was negatively correlated with the level of fasting blood sugar, and positively correlated with the level of fasting insulin. Our conclusions are: There are two ways of reducing blood sugar: one is by insulin, and the other is by IGF-I. IRT can reflect the former better, and IGF-I the latter. The combination of these two is of significant value in diagnosis and treatment of DM

  5. Polysomnographic sleep, growth hormone insulin-like growth factor-I axis, leptin, and weight loss

    DEFF Research Database (Denmark)

    Rasmussen, Michael; Wildschiødtz, Gordon; Juul, Anders

    2008-01-01

    severely obese subjects (BMI: 41+/-1 kg/m(2), 32+/-2 years of age), cross-sectional at baseline, and longitudinal after a dramatically diet-induced weight loss (36+/-7 kg). Ten age- and gender-matched nonobese subjects served as controls. Sleep duration (360+/-17 vs. 448+/-15 min/night; P... compared with nonobese subjects After diet-induced weight loss the differences in GH, free IGF-I, and leptin were no longer present between previously obese and nonobese subjects, whereas a significant difference in sleep duration and total IGF-I levels persisted. Rapid eye movement (REM) sleep, non......Short sleep appears to be strongly associated with obesity and altered metabolic function, and sleep and growth hormone (GH) secretion seems interlinked. In obesity, both the GH-insulin-like-growth-factor-I (GH-IGF-I) axis and sleep have been reported to be abnormal, however, no studies have...

  6. Señalización asociada al receptor del factor de crecimiento similar a la insulina de tipo I en una línea celular colombiana de carcinoma mamario

    Directory of Open Access Journals (Sweden)

    Wilson Mejía

    2010-12-01

    Conclusiones. El IGF-IR y la vía MAPK cinasa que involucra las proteínas ERK1/2 muestran una fosforilación mayor en las células 1595 a la observada en las MCF-7. El IGF-IR, principal activador de esta vía, podría jugar un papel importante en los procesos de proliferación y metástasis de tumores de cáncer de mama ductal infiltrante.

  7. 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...

  8. The spt5 C-terminal region recruits yeast 3' RNA cleavage factor I.

    Science.gov (United States)

    Mayer, Andreas; Schreieck, Amelie; Lidschreiber, Michael; Leike, Kristin; Martin, Dietmar E; Cramer, Patrick

    2012-04-01

    During transcription elongation, RNA polymerase II (Pol II) binds the general elongation factor Spt5. Spt5 contains a repetitive C-terminal region (CTR) that is required for cotranscriptional recruitment of the Paf1 complex (D. L. Lindstrom et al., Mol. Cell. Biol. 23:1368-1378, 2003; Z. Zhang, J. Fu, and D. S. Gilmour, Genes Dev. 19:1572-1580, 2005). Here we report a new role of the Spt5 CTR in the recruitment of 3' RNA-processing factors. Chromatin immunoprecipitation (ChIP) revealed that the Spt5 CTR is required for normal recruitment of pre-mRNA cleavage factor I (CFI) to the 3' ends of Saccharomyces cerevisiae genes. RNA contributes to CFI recruitment, as RNase treatment prior to ChIP further decreases CFI ChIP signals. Genome-wide ChIP profiling detected occupancy peaks of CFI subunits around 100 nucleotides downstream of the polyadenylation (pA) sites of genes. CFI recruitment to this defined region may result from simultaneous binding to the Spt5 CTR, to nascent RNA containing the pA sequence, and to the elongating Pol II isoform that is phosphorylated at serine 2 (S2) residues in its C-terminal domain (CTD). Consistent with this model, the CTR interacts with CFI in vitro but is not required for pA site recognition and transcription termination in vivo.

  9. Diminished concentrations of insulin-like growth factor I in cystic fibrosis

    DEFF Research Database (Denmark)

    Laursen, Erik; Juul, A; Lanng, S

    1995-01-01

    on IGF-I in cystic fibrosis are sparse and conflicting. From 1990-3, 235 of our 240 patients (114 males, 121 females, median age 16.2 years, ranged 0.1-44.0 years) had IGF-I measured once by radioimmunoassay. IGF-I was significantly reduced compared with a healthy Scandinavian control population: mean......Cystic fibrosis is frequently accompanied by a catabolic condition with low body mass index caused by a number of disease complications. Insulin-like growth factor-I (IGF-I) is an anabolic hormone and an important marker of nutritional status, liver function, and linear growth. Available data...... (-2 SD to +2 SD) IGF-I SD score was -0.97 (-3.7 to 1.7) in males and -0.67 (-3.2 to 1.9) in females. Height SD score was -0.95 (-3.3 to 1.4) in males and -0.81 (-3.2 to 1.6) in females. In patients who were still in the growth period a significant correlation of IGF-I SD score to height SD score (r...

  10. Atypical hemolytic-uremic syndrome due to complement factor I mutation.

    Science.gov (United States)

    Almalki, Abdullah H; Sadagah, Laila F; Qureshi, Mohammed; Maghrabi, Hatim; Algain, Abdulrahman; Alsaeed, Ahmed

    2017-11-06

    Atypical hemolytic-uremic syndrome (aHUS) is a rare disease of complement dysregulation leading to thrombotic microangiopathy (TMA). Renal involvement and progression to end-stage renal disease are common in untreated patients. We report a 52-year-old female patient who presented with severe acute kidney injury, microangiopathic hemolytic anemia, and thrombocytopenia. She was managed with steroid, plasma exchange, and dialysis. Kidney biopsy shows TMA and renal cortical necrosis. Genetic analysis reveals heterozygous complement factor I (CFI) mutation. Eculizumab was initiated after 3 mo of presentation, continued for 9 mo, and stopped because of sustained hematologic remission, steady renal function, and cost issues. Despite this, the patient continued to be in hematologic remission and showed signs of renal recovery, and peritoneal dialysis was stopped 32 mo after initiation. We report a case of aHUS due to CFI mutation, which, to the best of our knowledge, has not been reported before in Saudi Arabia. Our case illustrates the challenges related to the diagnosis and management of this condition, in which a high index of suspicion and prompt treatment are usually necessary.

  11. Paclitaxel and trastuzumab treatment affects insulin growth factor I expression in breast cancer cell lines

    Directory of Open Access Journals (Sweden)

    Yu-Xian Qian

    2015-12-01

    Full Text Available Breast cancer is the most common type of cancers and second primary cause of death among women. Insulin-like growth factor I (IGF-1 signaling pathway plays a vital role in cancer cell survival, proliferation, chemotaxis and angiogenesis. In this study, the effect of combination of two drugs, paclitaxel and trastuzumab on IGF signaling and cell cycle arrest in breast cancer cell lines, T47D and Hs0578T were explored. The interaction of paclitaxel and trastuzumab on IGF-1 signaling pathway was studied with IGF-1 and phosphoinositide 3-kinase inhibitor, LY294002. The protein expression of IGF signaling molecules were reduced in the drug treated cancer cells. LY294002 and IGF-1 with paclitaxel and trastuzumab treatment inhibited phosphorylated Akt. During G0/G1 phase, cell cycle arrest and accumulation of apoptotic cells were observed in drug treated cancer cells. The synergistic effect of paclitaxel and trastuzumab decreased the multiplication of breast cancer cells by altering the expression of IGF-I signaling molecules. This combination proves to be one of the useful methods to treat breast cancer.

  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. Renal protein synthesis in diabetes mellitus: effects of insulin and insulin-like growth factor I

    International Nuclear Information System (INIS)

    Barac-Nieto, M.; Lui, S.M.; Spitzer, A.

    1991-01-01

    Is increased synthesis of proteins responsible for the hypertrophy of kidney cells in diabetes mellitus? Does the lack of insulin, and/or the effect of insulin-like growth factor I (IGFI) on renal tubule protein synthesis play a role in diabetic renal hypertrophy? To answer these questions, we determined the rates of 3H-valine incorporation into tubule proteins and the valine-tRNA specific activity, in the presence or absence of insulin and/or IGFI, in proximal tubule suspension isolated from kidneys of streptozotocin diabetic and control rats. The rate of protein synthesis increased, while the stimulatory effects of insulin and IGFI on tubule protein synthesis were reduced, early (96 hours) after induction of experimental diabetes. Thus, hypertrophy of the kidneys in experimental diabetes mellitus is associated with increases in protein synthesis, rather than with decreases in protein degradation. Factor(s) other than the lack of insulin, or the effects of IGFI, must be responsible for the high rate of protein synthesis present in the hypertrophying tubules of diabetic rats

  14. The role of insulin-like growth factor-I in the physiopathology of hearing

    Directory of Open Access Journals (Sweden)

    Silvia eMurillo-Cuesta

    2011-07-01

    Full Text Available Insulin like growth factor I (IGF-I belongs to the family of polypeptides of insulin, which play a central role in embryonic development and adult nervous system homeostasis by endocrine, autocrine and paracrine mechanisms. IGF-I is fundamental for the regulation of cochlear development, growth and differentiation, and its mutations are associated with hearing loss in mice and men. Low levels of IGF-I have been shown to correlate with different human syndromes showing hearing loss and with presbyacusis. Animal models are fundamental to understand the genetic, epigenetic, and environmental factors that contribute to human hearing loss. In the mouse, IGF-I serum levels decrease with ageing and there is a concomitant hearing loss and retinal degeneration. In the Igf1-/- null mouse, hearing loss is due to neuronal loss, poor innervation of the sensory hair cells and age-related stria vascularis alterations. In the inner ear, IGF-I actions are mediated by intracellular signaling networks, RAF, AKT and p38 MAPK protein kinases modulate the expression and activity of transcription factors, as AP1, MEF2, FoxM1 and FoxP3, leading to the regulation of cell cycle and metabolism. Therapy with rhIGF-I has been approved in humans for the treatment of poor linear growth and certain neurodegenerative diseases. This review will discuss these findings and their implications in new IGF-I-based treatments for the protection or repair of hearing loss.

  15. Insulin receptors

    International Nuclear Information System (INIS)

    Kahn, C.R.; Harrison, L.C.

    1988-01-01

    This book contains the proceedings on insulin receptors. Part A: Methods for the study of structure and function. Topics covered include: Method for purification and labeling of insulin receptors, the insulin receptor kinase, and insulin receptors on special tissues

  16. Effect of acute sleep deprivation and recovery on Insulin-like Growth Factor-I responses and inflammatory gene expression in healthy men.

    Science.gov (United States)

    Chennaoui, Mounir; Drogou, Catherine; Sauvet, Fabien; Gomez-Merino, Danielle; Scofield, Denis E; Nindl, Bradley C

    2014-01-01

    Acute sleep deprivation in humans has been found to increase inflammatory markers and signaling pathways in the periphery through a possible Toll-like receptor 4 (TLR-4). In addition, short duration sleep has been associated with low circulating total Insulin-like Growth Factor-I (IGF-I) concentrations. We aimed to determine whether a total sleep deprivation (TSD) protocol with recovery altered whole-blood gene expression of the proinflammatory cytokines TNF-α and IL-6, as well as TLR-4 expression, and to examine the relationship with circulating concentrations of the IGF-I system. Twelve healthy men participated in a five-day TSD (two control nights followed by one night of sleep deprivation and one night of recovery). Blood was sampled at 0800, before and after sleep deprivation (D2 and D4), and after recovery (D5). It is shown that 25 h of sleep deprivation (D4) induced significant increases in mRNA levels of TNF-α and its soluble receptor R1 (Precovery was sufficient to restore basal expression levels for TNF-α, sTNF-R1, TLR-4 and circulating IGF-I. Changes in TLR-4 mRNA levels during the protocol correlated positively with those of TNF-α and sTNF-R1 (r=0.393 and r=0.490 respectively), and negatively with circulating free IGF-I (r=-0.494). In conclusion, 25 h of sleep deprivation in healthy subjects is sufficient to induce transient and reversible genomic expression of the pro-inflammatory cytokine TNF-α and its R1 receptor, and its mediator TLR-4, with a possible link to IGF-I axis inhibition.

  17. The roles of integrins and extracellular matrix proteins in the insulin-like growth factor I-stimulated chemotaxis of human breast cancer cells.

    Science.gov (United States)

    Doerr, M E; Jones, J I

    1996-02-02

    The effects of insulin-like growth factor I (IGF-I) on the migration of two human breast cancer cell lines, MCF-7 and MDA-231, were examined using a modified Boyden chamber. 10 ng/ml was the optimal IGF-I concentration for stimulation of migration. The majority of IGF-I-stimulated migration in both cell types was due to chemotaxis. MCF-7 cells failed to migrate on membranes coated with gelatin or fibronectin and migrated only in small numbers on laminin. In contrast, when vitronectin- or type IV collagen-coated membranes were used, the MCF-7 cells migrated in large numbers specifically in response to IGF-I but not to 10% fetal calf serum, epidermal growth factor, fibroblast growth factor, or platelet derived growth factor-BB. An IGF-I receptor-blocking antibody inhibited IGF-I-stimulated migration in both cell types. In addition, a blocking antibody to the alpha v beta 5 integrin (a vitronectin receptor) inhibited migration of MCF-7 cells in response to IGF-I through vitronectin but not through type IV collagen. Similarly, blocking antibodies specific for alpha 2 and beta 1 integrins significantly inhibited migration of both cell types through type IV collagen-coated membranes but not through vitronectin-coated membranes. We conclude that: 1) IGF-I stimulates migration of these two cell types through the IGF-I receptor; 2) interaction of vitronectin with the alpha v beta 5 integrin or collagen with the alpha 2 beta 1 integrin is necessary for the complete IGF-I response in MCF-7 cells, and 3) because migration represents an in vitro model for metastatic spread, integrins, extracellular matrix proteins, and IGF-I may play coordinated roles in the metastasis of breast cancer in vivo.

  18. Little effects of Insulin-like Growth Factor-I on testicular atrophy induced by hypoxia

    Directory of Open Access Journals (Sweden)

    Casares Amelia

    2006-02-01

    Full Text Available Abstract Background Insulin-like Growth Factor-I (IGF-I supplementation restores testicular atrophy associated with advanced liver cirrhosis that is a condition of IGF-I deficiency. The aim of this work was to evaluate the effect of IGF-I in rats with ischemia-induced testicular atrophy (AT without liver disease and consequently with normal serum level of IGF-I. Methods Testicular atrophy was induced by epinephrine (1, 2 mg/Kg intra-scrotal injection five times per week during 11 weeks. Then, rats with testicular atrophy (AT were divided into two groups (n = 10 each: untreated rats (AT receiving saline sc, and AT+IGF, which were treated with IGF-I (2 μg.100 g b.w.-1.day-1, sc. for 28d. Healthy controls (CO, n = 10 were studied in parallel. Animals were sacrificed on day 29th. Hypophyso-gonadal axis, IGF-I and IGFBPs levels, testicular morphometry and histopathology, immuno-histochemical studies and antioxidant enzyme activity phospholipid hydroperoxide glutathione peroxidase (PHGPx were assessed. Results Compared to controls, AT rats displayed a reduction in testicular size and weight, with histological testicular atrophy, decreased cellular proliferation and transferrin expression, and all of these alterations were slightly improved by IGF-I at low doses. IGF-I therapy increased signifincantly steroidogenesis and PHGPx activity (p Conclusion In testicular atrophy by hypoxia, condition without IGF-I deficiency, IGF-treatment induces only partial effects. These findings suggest that IGF-I therapy appears as an appropriate treatment in hypogonadism only when this is associated to conditions of IGF-I deficiency (such as Laron Syndrom or liver cirrhosis.

  19. [Insulin-like growth factor I (IGF-I) and liver cirrhosis].

    Science.gov (United States)

    Conchillo, M; Prieto, J; Quiroga, J

    2007-03-01

    Insulin-like growth factor I (IGF-I) is a polypeptide hormone secreted by multiple tissues in response to growth hormone (GH). It is partly responsible for GH activity, and also has glucose-lowering and anabolizing effects. Ninety percent of circulating IGF-I originates in the liver and has autocrine, paracrine, and endocrine effects, the latter on multiple tissues. Liver cirrhosis results in a progressive decline of hepatic IGF-I output, and this factor may become undetectable in advanced disease. Some cirrhosis complications, mainly those nutritional and metabolic in nature (insuline resistance, malnutrition, osteopenia, hypogonadism, intestinal disorders), may be at least partly related to this IGF-I deficiency, since some IGF-I effects represent a reverse image of cirrhosis complications. Despite this, IGF-I replacement therapy has been never suggested for cirrhosis. A number of experimental studies in cirrhotic rats showed that therapy using low-dose recombinant IGF-I exerts two types of effect on experimental cirrhosis: a) liver improvement driven by improved hepatocellular function, portal hypertension, and liver fibrosis; and b) cirrhosis-related extrahepatic disorder improvement driven by improved food efficiency, muscle mass, bone mass, gonadal function and structure, and intestinal function and structure, with a normalization of sugar and amino acid malabsorption, and improved intstinal barrier function, manifested by reduced endotoxemia and bacterial translocation. Subsequently, the first randomized, double-blind, placebo-controlled, pilot clinical trial in a small number of cirrhotic patients showed increased serum albumin and improved energy metabolism as a result of IGF-I use. Further clinical trials are needed to identify adequate IGF-I doses, administration duration and frequency, and the subgroup of cirrhotic patients who will benefit most from this replacement therapy.

  20. The correlations between insulin-like growth factor I, insulin and gestational diabetes mellitus

    International Nuclear Information System (INIS)

    Xu Yongle; Yang Weiwen; Pu Xiangke

    2006-01-01

    Objectives; To research the correlation between insulin-like growth factor I (IGF-I), insulin and gestational diabetes mellitus (GDM). Methods: Thirty cases of GDM are taken as the GDM group. Thirty cases of normal pregnant women were taken as the control group. The insulin in maternal serum of these two groups were measured at 31 ± 1 weeks gestational age by radioimmunity. The IGF-I in maternal serum at 31 ± 1 weeks gestational age and IGF-I in umbilical serum at term delivery were measured by ELISA. results: There was no significant difference in IGF-I level in maternal serum between the GDM group and the control group (P>0.05) and there was significant difference between these two groups maternal LnIRI, IGF-I in umbilical serum and weight of newborn baby (P<0.01). In the GDM group, the IGF-I in maternal serum positively correlated with the LnIRI (r=0.424, P<0.05) and IGF-I in umbilical serum positively correlated with the weight of new-born baby (r=0.434, P<0.05). Conclusion: GDM has serious insulin resistance. The IGF-I in maternal serum correlated with the IR in GDM. IGF-I in umbilical serum plays a role in the pathology and physiology process of fetal macrosomia. Abnormality of the axis of growth hormone-insulin-insulin-like growth factor caused by IGF-I might be through the way of insulin resistance, and GDM is resulted. (authors)

  1. Insulin-like growth factor I has independent effects on bone matrix formation and cell replication

    International Nuclear Information System (INIS)

    Hock, J.M.; Centrella, M.; Canalis, E.

    1988-01-01

    The effects of insulin-like growth factor-I (IGF-I) and insulin on bone matrix synthesis and bone cell replication were studied in cultured 21-day-old fetal rat calvariae. Histomorphometry techniques were developed to measure the incorporation of [2,3- 3 H]proline and [methyl- 3 H]thymidine into bone matrix and bone cell nuclei, respectively, using autoradiographs of sagittal sections of calvariae cultured with IGF-I, insulin, or vehicle for up to 96 h. To confirm an effect on bone formation, IGF-I was also studied for its effects on [ 3 H]proline incorporation into collagenase-digestible protein (CDP) and noncollagen protein and on [ 3 H]thymidine incorporation into acid-precipitable material (DNA). IGF-I at 10(-9)-10(-7) M significantly increased the rate of bone matrix apposition and CDP after 24 h by 45-50% and increased cell labeling by 8-fold in the osteoprogenitor cell zone, by 4-fold in the osteoblast cell zone, and by 2-fold in the periosteal fibroblast zone. Insulin at 10(-9)-10(-6) M also increased matrix apposition rate and CDP by 40-50%, but increased cell labeling by 2-fold only at a concentration of 10(-7) M or higher and then only in the osteoprogenitor cell zone. When hydroxyurea was added to IGF-I-treated bones, the effects of IGF-I on DNA synthesis were abolished, but the increase in bone matrix apposition induced by IGF-I was only partly diminished. In conclusion, IGF-I stimulates matrix synthesis in calvariae, an effect that is partly, although not completely, dependent on its stimulatory effect on DNA synthesis

  2. Effects of insulin-like growth factor I or human growth hormone in fasted rats.

    Science.gov (United States)

    Asakawa, K; Hizuka, N; Takano, K; Horikawa, R; Sukegawa, I; Demura, H; Shizume, K

    1992-03-01

    To study the effect of insulin-like growth factor I (IGF-I) treatment on growth and metabolism in fasted rats and compare it with the effect of human growth hormone (hGH), we infused 120 micrograms/ml IGF-I continuously or injected 200 micrograms hGH twice a day in fasted rats. After a 3 1/2-day administration of IGF-I in fasted rats, the body weights, kidney, spleen and adrenal gland weights were greater than those for untreated fasted rats (control). The body weights and the organ weights in hGH treated rats did not differ from those in control rats. Serum IGF-I levels in control, hGH treated and IGF-I treated rats were 64.0 +/- 6.1, 107.5 +/- 6.9 and 129.8 +/- 6.3 ng/ml, respectively, which were significantly different from each other. Blood urea nitrogen (BUN) levels were 13.9 +/- 1.1 ng/ml in IGF-I treated rats, which were significantly lower than those of control rats. Human GH treatment did not change BUN but affected nonesterified fatty acid (NEFA) and triglyceride. In IGF-I treated rats three-day urinary excretion of nitrogen and creatine were 163.5 +/- 14.6 mg and 9.53 +/- 1.53 mg, which were significantly less than those in control rats. These data indicate that IGF-I infusion inhibits body weight loss and catabolism in fasted rats and might be a useful therapy in catabolic conditions.

  3. Growth hormone increases and insulin-like growth factor-I decreases circulating lipoprotein(a)

    Science.gov (United States)

    Laron, Z; Wang, X L; Klinger, B; Silbergeld, A; Wilcken, D E

    1997-04-01

    Elevated serum lipoprotein(a) (Lp(a)) is a strong risk factor for coronary artery disease (CAD). Genetic factors appear to account for the major variance in Lp(a) levels but the contribution hormones make in modulating Lp(a) levels is not yet clear. In the present investigation we determined the effects of human growth hormone (hGH) and insulin-like growth factor-I (IGF-I) on circulating Lp(a). Four groups of patients were studied. Group a: adults with GH deficiency (n = 7) treated with hGH (0.05 U/kg/day, s.c.); group b: girls with Turner syndrome (n = 7) treated with hGH (0.1 U/kg/day, s.c.); group c: prepubertal boys with idiopathic short stature (n = 6) treated with the GH secretagogue (GHRP) hexarelin (60 micrograms t.i.d. intranasally); group d: Laron syndrome patients (n = 10) treated with IGF-I (100-200 micrograms/kg/day, s.c.). Following overnight fasting, serum was sampled before the initiation of treatment and during 6-9 months treatment. Serum IGF-I rose significantly in all the subjects in all four groups. In the first three groups in which IGF-I was elevated by exogenous or endogenous GH stimulation, serum Lp(a) increased significantly (119 +/- 35%, P hGH or GHRP (65.2 +/- 31%, P = 0.109; 93.7 +/- 53%, P = 0.062; 353.8 +/- 52.7%, P hGH in children and adults and the role of Lp(a) as a CAD risk factor.

  4. Plasma leptin and insulin-like growth factor I levels during acute exacerbations of chronic obstructive pulmonary disease

    OpenAIRE

    Kythreotis, Prokopis; Kokkini, Ageliki; Avgeropoulou, Stavrina; Hadjioannou, Argyro; Anastasakou, Efgenia; Rasidakis, Antonis; Bakakos, Petros

    2009-01-01

    Abstract Background Recent studies have provided evidence for a link between leptin and tumor necrosis factor-alpha (TNF-α). Insulin-like growth factor I (IGF-I) mediates the metabolic effects of growth hormone (GH). The GH axis is believed to be suppressed in chronic obstructive pulmonary disease (COPD). The aim of this study is to find out whether acute exacerbations of COPD are followed by changes in plasma leptin and insulin-like growth factor I (IGF-I) levels and furthermore, whether the...

  5. Low serum insulin-like growth factor I is associated with increased risk of ischemic heart disease

    DEFF Research Database (Denmark)

    Juul, Anders; Scheike, Thomas Harder; Davidsen, Michael

    2002-01-01

    Insulin-like growth factor I (IGF-I) has been suggested to be involved in the pathogenesis of atherosclerosis. We hypothesize that low IGF-I and high IGFBP-3 levels might be associated with increased risk of ischemic heart disease (IHD).......Insulin-like growth factor I (IGF-I) has been suggested to be involved in the pathogenesis of atherosclerosis. We hypothesize that low IGF-I and high IGFBP-3 levels might be associated with increased risk of ischemic heart disease (IHD)....

  6. Exercise-induced insulin-like growth factor I system concentrations after training in women.

    Science.gov (United States)

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

    2013-03-01

    This study examined the effects of short-term physical training on the acute hormonal response (i.e., growth hormone, total and free insulin-like growth factor I [IGF-I], and IGF binding proteins [IGFBP]-1, IGFBP-2, and IGFBP-3) to resistance exercise (RE) in women. Forty-six women (20.3 ± 0.3 yr, mass = 64.1 ± 7.3 kg, height = 165.7 ± 1.0 cm) were randomly assigned to an endurance training (E), resistance training (R), combined training (R + E), or control (C) group for 8wk. Subjects completed a standardized bout of RE (six sets of back squats at 10 repetition maximum) before and after training. Blood samples were obtained at rest (PRE), after the third set, immediately postexercise (POST), and at 15 min and 30 min after exercise. Acute RE significantly increased (P change from PRE to POST = +10.9 ± 7.5 μg·L-1), total IGF-I (+66.1 ± 25.4 μg·L-1), IGFBP-1 (+2.5 ± 3.1 μg·L-1), IGFBP-2 (+86.0 ± 86.8 μg·L-1), and IGFBP-3 (+0.69 ± 0.25 mg·L-1) concentrations and decreased free IGF-I concentrations (-0.14 ± 0.21 μg·L-1). After 8 wk of training, total IGF-I concentrations were significantly increased (change in POST concentrations from week 0 to week 8 = +82.5 ± 120.8 μg·L-1), and IGFBP-1 concentrations were significantly decreased (-6.7 ± 13.6 μg·L-1) during exercise in groups that participated in resistance training (R and R + E); no significant changes were seen after E or C. Participation in resistance training increased total IGF-I and reduced IGFBP-1 concentrations during acute RE, indicating exercise mode-specific adaptations in the circulating IGF-I system.

  7. Astrocytes require insulin-like growth factor I to protect neurons against oxidative injury [v1; ref status: indexed, http://f1000r.es/2lf

    Directory of Open Access Journals (Sweden)

    Laura Genis

    2014-01-01

    Full Text Available Oxidative stress is a proposed mechanism in brain aging, making the study of its regulatory processes an important aspect of current neurobiological research. In this regard, the role of the aging regulator insulin-like growth factor I (IGF-I in brain responses to oxidative stress remains elusive as both beneficial and detrimental actions have been ascribed to this growth factor. Because astrocytes protect neurons against oxidative injury, we explored whether IGF-I participates in astrocyte neuroprotection and found that blockade of the IGF-I receptor in astrocytes abrogated their rescuing effect on neurons. The protection mediated by IGF-I against oxidative stress (H2O2 in astrocytes is probably needed for these cells to provide adequate neuroprotection. Indeed, in astrocytes but not in neurons, IGF-I helps decrease the pro-oxidant protein thioredoxin-interacting protein 1 and normalizes the levels of reactive oxygen species. Furthermore, IGF-I cooperates with trophic signals produced by astrocytes in response to H2O2 such as stem cell factor (SCF to protect neurons against oxidative insult. After stroke, a condition associated with brain aging where oxidative injury affects peri-infarcted regions, a simultaneous increase in SCF and IGF-I expression was found in the cortex, suggesting that a similar cooperative response takes place in vivo. Cell-specific modulation by IGF-I of brain responses to oxidative stress may contribute in clarifying the role of IGF-I in brain aging.

  8. The C-terminal domain of the nuclear factor I-B2 isoform is glycosylated and transactivates the WAP gene in the JEG-3 cells

    International Nuclear Information System (INIS)

    Mukhopadhyay, Sudit S.; Rosen, Jeffrey M.

    2007-01-01

    The transcription factor nuclear factor I (NFI) has been shown previously both in vivo and in vitro to be involved in the cooperative regulation of whey acidic protein (WAP) gene transcription along with the glucocorticoid receptor and STAT5. In addition, one of the specific NFI isoforms, NFI-B2, was demonstrated in transient co-transfection experiments in JEG cells, which lack endogenous NFI, to be preferentially involved in the cooperative regulation of WAP gene expression. A comparison of the DNA-binding specificities of the different NFI isoforms only partially explained their differential ability to activate the WAP gene transcription. Here, we analyzed the transactivation regions of two NFI isoforms by making chimeric proteins between the NFI-A and B isoforms. Though, their DNA-binding specificities were not altered as compared to the corresponding wild-type transcription factors, the C-terminal region of the NFI-B isoform was shown to preferentially activate WAP gene transcription in cooperation with GR and STAT5 in transient co-transfection assays in JEG-3 cells. Furthermore, determination of serine and threonine-specific glycosylation (O-linked N-acetylglucosamine) of the C-terminus of the NFI-B isoform suggested that the secondary modification by O-GlcNAc might play a role in the cooperative regulation of WAP gene transcription by NFI-B2 and STAT5

  9. Astrocytes require insulin-like growth factor I to protect neurons against oxidative injury [v2; ref status: indexed, http://f1000r.es/38u

    Directory of Open Access Journals (Sweden)

    Laura Genis

    2014-04-01

    Full Text Available Oxidative stress is a proposed mechanism in brain aging, making the study of its regulatory processes an important aspect of current neurobiological research. In this regard, the role of the aging regulator insulin-like growth factor I (IGF-I in brain responses to oxidative stress remains elusive as both beneficial and detrimental actions have been ascribed to this growth factor. Because astrocytes protect neurons against oxidative injury, we explored whether IGF-I participates in astrocyte neuroprotection and found that blockade of the IGF-I receptor in astrocytes abrogated their rescuing effect on neurons. We found that IGF-I directly protects astrocytes against oxidative stress (H2O2. Indeed, in astrocytes but not in neurons, IGF-I decreases the pro-oxidant protein thioredoxin-interacting protein 1 and normalizes the levels of reactive oxygen species. Furthermore, IGF-I cooperates with trophic signals produced by astrocytes in response to H2O2 such as stem cell factor (SCF to protect neurons against oxidative insult. After stroke, a condition associated with brain aging where oxidative injury affects peri-infarcted regions, a simultaneous increase in SCF and IGF-I expression was found in the cortex, suggesting that a similar cooperative response takes place in vivo. Cell-specific modulation by IGF-I of brain responses to oxidative stress may contribute in clarifying the role of IGF-I in brain aging.

  10. Targeting 3-phosphoinoside-dependent kinase-1 to inhibit insulin-like growth factor-I induced AKT and p70 S6 kinase activation in breast cancer cells.

    Directory of Open Access Journals (Sweden)

    Sangita M Baxi

    Full Text Available Binding of IGF to IGF-IR activates PI3K to generate PIP3 which in turn recruits and activates proteins that contain a pleckstrin homology (PH domain, including AKT and PDK1. PDK1 is highly expressed in breast tumor samples and breast cancer cell lines. Here we demonstrate that targeting PDK1 with the potent and selective PDK1 inhibitor PF-5177624 in the IGF-PI3K pathway blocks breast cancer cell proliferation and transformation. Breast cancer cell lines MCF7 and T47D, representing the luminal ER positive subtype and harboring PIK3CA mutations, were most responsive to IGF-I induction resulting in upregulated AKT and p70S6K phosphorylation via PDK1 activation. PF-5177624 downregulated AKT and p70S6K phosphorylation, blocked cell cycle progression, and decreased cell proliferation and transformation to block IGFR-I induced activation in breast cancer cells. These results may provide insight into clinical strategies for developing an IGFR-I inhibitor and/or a PDK1 inhibitor in luminal breast cancer patients.

  11. Complement factor I deficiency: a not so rare immune defect. Characterization of new mutations and the first large gene deletion

    Directory of Open Access Journals (Sweden)

    Alba-Domínguez María

    2012-06-01

    Full Text Available Abstract Background Complement Factor I (CFI is a serine protease with an important role in complement alternative pathway regulation. Complete factor I deficiency is strongly associated with severe infections. Approximately 30 families with this deficiency have been described worldwide. Patients and methods We have studied five new Spanish families suffering from CFI deficiency. From 19 screened people, 7 homozygous, 10 heterozygous and 2 healthy subjects were identified. Clinical, biochemical and genetic descriptions are included. Results Molecular studies demonstrated 4 novel mutations in the screened individuals; amongst them, we describe here the first great gene deletion reported in the CFI locus, which includes full exon 2 and part of the large intron 1. Conclusion CFI deficiency is possibly an underestimated defect and the eventual existence of this deficiency should be tested in those patients exhibiting low C3 and recurrent bacterial infections. We propose a simple diagnostic flowchart to help clinicians in the identification and correct diagnosis of such patients.

  12. The pubertal spurt: effects of sex steroids on growth hormone and insulin-like growth factor I.

    Science.gov (United States)

    Caufriez, A

    1997-02-01

    In puberty, the growth spurt and the appearance of secondary sex characteristics occur concomitantly with an increase of sex steroids, growth hormone (GH) and insulin-like growth factor I (IGF-I). A number of experiments indicate that sex steroids exert a stimulatory action on the somatotropic axis. This effect is due to an amplifying action of oestradiol (secreted by the ovaries or after testosterone aromatization) on the neuroendocrine regulation of pulsatile GH release.

  13. Hormones and diet: low insulin-like growth factor-I but normal bioavailable androgens in vegan men

    Science.gov (United States)

    Allen, N E; Appleby, P N; Davey, G K; Key, T J

    2000-01-01

    Mean serum insulin-like growth factor-I was 9% lower in 233 vegan men than in 226 meat-eaters and 237 vegetarians (P = 0.002). Vegans had higher testosterone levels than vegetarians and meat-eaters, but this was offset by higher sex hormone binding globulin, and there were no differences between diet groups in free testosterone, androstanediol glucuronide or luteinizing hormone. © 2000 Cancer Research Campaign PMID:10883675

  14. Evidence for the possible biological significance of the igf-1 gene alternative splicing in prostate cancer

    Directory of Open Access Journals (Sweden)

    Anastassios ePhilippou

    2013-03-01

    Full Text Available Insulin-like growth factor I (IGF-I has been implicated in the pathogenesis of prostate cancer (PCa, since it plays a key role in cell proliferation, differentiation and apoptosis. The IGF-I actions are mediated mainly via its binding to the type I IGF receptor (IGF-IR, however IGF-I signaling via insulin receptor (IR and hybrid IGF-I/IR is also evident. Different IGF-I mRNA splice variants, namely IGF-IEa, IGF-IEb and IGF-IEc, are expressed in human cells and tissues. These transcripts encode several IGF-I precursor proteins which contain the same bioactive product (mature IGF-I, however, they differ by the length of their signal peptides on the amino-terminal end and the structure of the extension peptides (E-peptides on the carboxy-terminal end. There is an increasing interest in the possible different role of the IGF-I transcripts and their respective non-(matureIGF-I products in the regulation of distinct biological activities. Moreover, there is strong evidence of a differential expression profile of the IGF-I splice variants in normal vs. PCa tissues and PCa cells, implying that the expression pattern of the various IGF-I transcripts and their respective protein products may possess different functions in cancer biology. Herein, the evidence that the IGF-IEc transcript regulates PCa growth via Ec-peptide specific and IGF-IR/IR-independent signaling is discussed.

  15. Effects of immune challenge on concentrations of serum insulin-like growth factor-I and growth performance in pigs.

    OpenAIRE

    Hevener, W; Routh, P A; Almond, G W

    1999-01-01

    This study was designed to determine the long-term effects of repeated endotoxin treatment or immunization against human serum albumin on concentrations of serum insulin-like growth factor-I (IGF-I) and other indicators of growth performance in growing pigs. Thirty gilts (38.5 +/- 0.9 kg) were randomly assigned to 5 treatment groups (n = 6 animals/group): 1) lipopolysaccharide injections, 2) lipopolysaccharide pair-fed, 3) human serum albumin immunization, 4) human serum albumin pair-fed, and...

  16. Rearing Mozambique tilapia in tidally-changing salinities: Effects on growth and the growth hormone/insulin-like growth factor I axis.

    Science.gov (United States)

    Moorman, Benjamin P; Yamaguchi, Yoko; Lerner, Darren T; Grau, E Gordon; Seale, Andre P

    2016-08-01

    The growth hormone (GH)/insulin-like growth factor (IGF) axis plays a central role in the regulation of growth in teleosts and has been shown to be affected by acclimation salinity. This study was aimed at characterizing the effects of rearing tilapia, Oreochromis mossambicus, in a tidally-changing salinity on the GH/IGF axis and growth. Tilapia were raised in fresh water (FW), seawater (SW), or in a tidally-changing environment, in which salinity is switched between FW (TF) and SW (TS) every 6h, for 4months. Growth was measured over all time points recorded and fish reared in a tidally-changing environment grew significantly faster than other groups. The levels of circulating growth hormone (GH), insulin-like growth factor I (IGF-I), pituitary GH mRNA, gene expression of IGF-I, IGF-II, and growth hormone receptor 2 (GHR) in the muscle and liver were also determined. Plasma IGF-I was higher in FW and TS than in SW and TF tilapia. Pituitary GH mRNA was higher in TF and TS than in FW and SW tilapia. Gene expression of IGF-I in the liver and of GHR in both the muscle and liver changed between TF and TS fish. Fish growth was positively correlated with GH mRNA expression in the pituitary, and GHR mRNA expression in muscle and liver tissues. Our study indicates that rearing fish under tidally-changing salinities elicits a distinct pattern of endocrine regulation from that observed in fish reared in steady-state conditions, and may provide a new approach to increase tilapia growth rate and study the regulation of growth in euryhaline fish. Copyright © 2016 Elsevier Inc. All rights reserved.

  17. Somatostatin receptors

    DEFF Research Database (Denmark)

    Møller, Lars Neisig; Stidsen, Carsten Enggaard; Hartmann, Bolette

    2003-01-01

    therefore been acknowledged to be a third endogenous ligand at SRIF receptors. This review goes through mechanisms of signal transduction, pharmacology, and anatomical distribution of SRIF receptors. Structurally, SRIF receptors belong to the superfamily of G protein-coupled (GPC) receptors, sharing....... The generation of knock-out (KO) mice, intended as a means to define the contributions made by individual receptor subtypes, necessarily marks but an approximation. Furthermore, we must now take into account the stunning complexity of receptor co-operation indicated by the observation of receptor homo......-peptides, receptor agonists and antagonists. Relatively long half lives, as compared to those of the endogenous ligands, have been paramount from the outset. Motivated by theoretical puzzles or the shortcomings of present-day diagnostics and therapy, investigators have also aimed to produce subtype...

  18. Differential expression of insulin like growth factor I and other fibroblast mitogens in porcine colostrum and milk

    Energy Technology Data Exchange (ETDEWEB)

    Tan, T.J.; Simmen, R.C.M.; Simmen, F.A.

    1987-05-01

    Sow mammary secretions contain at least 3 distinct growth factor activities, distinguished by their size and relative abundance in colostrum or later milk. Gel filtration of colostrum in Sephadex G-200 columns, followed by acid-ethanol extraction and radioimmunoassay (RIA) for insulin like growth factor I (IGF-I) revealed high levels of this factor in the 150K and 50K MW regions, characteristic of IGF-I: binding protein complexes. Acid treatment of these fractions yielded free IGF-I peptide (7.5K). Parallel mitogen assays with a fibroblast cell line (AKR-2B) demonstrated a predominant peak of high MW activity (sow colostral growth factor-I, SCGF-I) eluting near the column void volume (MW > 150K). Treatment of SCGF-I with 1M acetic acid resulted in a size reduction of the mitogenic activity (MW < 10K), suggesting association of SCGF-I with a binding protein. The SCGF-I peptide was noncompetitive in IGF-I RIA, was distinct in MW from free IGF-I, and was not mitogenic for chick embryo fibroblasts. Sow milk contains less IGF-I and SCGF-I but does display a predominant peak of small MW (approx. 3K) AKR-2B activity. The changes in expression of these growth factors during lactation may reflect differing roles in lactogenesis and/or neonatal growth and development.

  19. Effects of phorbol ester and staurosporine on the actions of insulin-like growth factor-I on rat ovarian granulosa cells.

    Science.gov (United States)

    He, H; Herington, A C; Roupas, P

    1995-02-01

    Insulin-like growth factor I (IGF-I) is able to stimulate ovarian granulosa cell steroidogenesis induced by gonadotopins. This gonadotropin-induced potentiation of IGF-I action appears to be due, at least in part, to a gonadotropin-induced increase in membrane-bound IGF-I receptor number and/or decrease in extracellular IGF binding proteins (IGFBPs). Protein kinase C (PKC) has recently been reported to inhibit gonadotropin-induced steroidogenesis in rat ovarian granulosa cells. The role of PKC in the effects of IGF-I on gonadotropin action, however, is unknown. In this study, the effects of phorbol 12-myristate 13-acetate (PMA, a PKC activator) and staurosporine (ST, a PKC inhibitor) on IGF-I action were studied using immature rat ovarian granulosa cells. Activation of PKC by PMA did not affect steroidogenesis or cAMP secretion in cells treated with or without IGF-I. On the other hand, inhibition of PKC by ST alone (10(-9)-10(-7)m) led to an increase in progesterone production in a dose- and time-dependent manner without affecting cAMP secretion. In the presence, but not absence, of ST, IGF-I was able to stimulate progesterone production in the absence of any gonadotropin. PMA decreased ST-induced steroidogenesis and essentially abolished ST-potentiated IGF-I stimulation of steroidogenesis, suggesting the effects of ST on IGF-I action involved a PKC-dependent mechanism. Unlike gonadotropin, ST did not change IGF-I receptor binding. However, ST significantly decreased a major IGF binding protein (IGFBP, ∼30kDa) which is likely to be IGFBP-5, whereas it increased a minor IGFBP (∼24kDa) which is likely to be IGFBP-4. Both effects of ST were dose- and time-dependent. Furthermore, ST inhibited the expression of mRNA for IGFBP-5 suggesting that ST decreased IGFBP-5 levels by inhibiting its transcription and/or decreasing the stability of its mRNA. Interestingly, ST also decreased mRNA levels of IGFBP-4 despite a significant increase in secreted IGFBP-4 levels. The

  20. Retardation of fetal dendritic development induced by gestational hyperglycemia is associated with brain insulin/IGF-I signals.

    Science.gov (United States)

    Jing, Yu-Hong; Song, Yan-Feng; Yao, Ya-Ming; Yin, Jie; Wang, De-Gui; Gao, Li-Ping

    2014-10-01

    Hyperglycemia is an essential risk factor for mothers and fetuses in gestational diabetes. Clinical observation has indicated that the offspring of mothers with diabetes shows impaired somatosensory function and IQ. However, only a few studies have explored the effects of hyperglycemia on fetal brain development. Neurodevelopment is susceptible to environmental conditions. Thus, this study aims to investigate the effects of maternal hyperglycemia on fetal brain development and to evaluate insulin and insulin-like growth factor-I (IGF-I) signals in fetal brain under hyperglycemia or controlled hyperglycemia. At day 1 of pregnancy, gestational rats were intraperitoneally injected with streptozocin (60 mg/kg). Some of the hyperglycemic gestational rats were injected with insulin (20 IU, two times a day) to control hyperglycemia; the others were injected with saline of equal volume. The gestational rats were sacrificed at days 14, 16, and 18 of embryo development. The dendritic spines of subplate cortex neurons in the fetal brain were detected by Golgi-Cox staining. The mRNA levels of insulin receptors (IRs) and IGF-IR in the fetal brain were measured using qRT-PCR. The protein levels of synaptophysin, IR, and IGF-IR in the fetal brain were detected by western blot. No significant difference in fetal brain formation was observed between the maternal hyperglycemic group and insulin-treated group. By contrast, obvious retardation of dendritic development in the fetus was observed in the maternal hyperglycemic group. Similarly, synaptophysin expression was lower in the fetus of the maternal hyperglycemic group than in that of the insulin-treated group. The mRNA and protein expression levels of IRs in the fetal brain were higher in the hyperglycemic group than in the insulin-treated group. By contrast, the levels of IGF-IR in the brain were lower in the fetus of the maternal hyperglycemic group than in that of the insulin-treated group. These results suggested that

  1. Somatostatin receptors

    DEFF Research Database (Denmark)

    Møller, Lars Neisig; Stidsen, Carsten Enggaard; Hartmann, Bolette

    2003-01-01

    therefore been acknowledged to be a third endogenous ligand at SRIF receptors. This review goes through mechanisms of signal transduction, pharmacology, and anatomical distribution of SRIF receptors. Structurally, SRIF receptors belong to the superfamily of G protein-coupled (GPC) receptors, sharing......- and heterodimerisation, let alone oligomerisation. Theoretically, this phenomenon adds a novel series of functional megareceptors/super-receptors, with varied pharmacological profiles, to the catalogue of monomeric receptor subtypes isolated and cloned in the past. SRIF analogues include both peptides and non......-peptides, receptor agonists and antagonists. Relatively long half lives, as compared to those of the endogenous ligands, have been paramount from the outset. Motivated by theoretical puzzles or the shortcomings of present-day diagnostics and therapy, investigators have also aimed to produce subtype...

  2. Stimulation of myenteric plexus neurite outgrowth by insulin and insulin-like growth factors I and II.

    Science.gov (United States)

    Mulholland, M W; Romanchuk, G; Simeone, D M; Flowe, K

    1992-01-01

    A defined culture medium containing insulin, insulin-like growth factor I (IGF-I) or insulin-like growth factor II (IGF-II) supported morphological development of myenteric plexus neurons derived from neonatal guinea pigs. Insulin increased neurite outgrowth 3-fold at concentrations as low as 0.2 nM. Similar significant and dose-dependent increases in neurite outgrowth were noted with IGF-I and IGF-II. Stimulation of neurite outgrowth was abolished by exposure to cytosine arabinofuranoside, an agent toxic to non-neuronal cells, implying that trophic effects of insulin or insulin-like growth factors require the presence of non-neuronal elements in culture.

  3. [Insulin-like growth factor-I and cognitive function in patients with obstructive sleep apnea syndrome].

    Science.gov (United States)

    Xu, Yan; Li, Shunwei; Huang, Xizhen; Cong, Bo

    2002-10-25

    To explore the possible biochemical mechanism of cognitive impairment in patients with obstructive sleep apnea syndrome (OSAS). Polysomnography was administered to thirty-six patients with OSAS and eighteen education and BMI-matched controls, all males aged 40 approximately 49 for 8.5 hours at night. Early next morning blood was drawn and serum insulin-like growth factor-I (IGF-I) was determined by immunoradiometric assay. Then neuropsychological tests of visual regeneration, digital symbol, comprehensive memory and digital span were conducted. The quality of sleep in the patients with OSAS was significantly worse than that of the controls. The score of visual regeneration in the patients with OSAS was 8.4 +/- 2.7, significantly lower than that in control group (11.6 +/- 1.4, P sleep duration (r = 0.598, P sleep deprivation may be the reason of the decrease of the serum IGF-I level in patients with OSAS.

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

    DEFF Research Database (Denmark)

    Hansen, Mette; Boesen, Anders; Holm, Lars

    2013-01-01

    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...

  5. Enzyme-linked immunosorbent assays for insulin-like growth factor-I using six-histidine tag fused proteins

    International Nuclear Information System (INIS)

    Huang Yong; Shi Ruina; Zhong Xuefei; Wang Dan; Zhao Meiping; Li Yuanzong

    2007-01-01

    The fusion proteins of insulin-like growth factor-I (IGF-I) and six-histidine tag (IGF-I-6H, 6H-IGF-I-6H) were cloned, expressed, purified and renatured, with their immunoreaction properties and biological activities intact. The binding kinetics between these fusion proteins and anti-IGF-I antibody or anti-6H antibody were studied using surface plasmon resonance (SPR). Two enzyme-linked immunosorbent assay (ELISA) modes, which proved feasible in the measurement of human serum samples, were used to detect IGF-I with the help of the six-histidine tagged proteins. Furthermore, combining the production technique of the six-histidine tagged fusion protein with the competitive sandwich ELISA mode, using an enzyme labeled anti-6H antibody as a tracer, can be a universal immunochemical method to quantitate other polypeptides or proteins

  6. Changes in calcitropic hormones, bone markers and insulin-like growth factor I (IGF-I) during pregnancy and postpartum

    DEFF Research Database (Denmark)

    Møller, U K; Streym, S; Mosekilde, L

    2013-01-01

    and 36 weeks postpartum. The controls were followed in parallel. RESULTS: P-estradiol (E2), prolactin and 1,25-dihydroxyvitamin D (1,25(OH)2D) increased (pgrowth factor I (IGF......UNLABELLED: Pregnancy and lactation cause major changes in calcium homeostasis and bone metabolism. This population-based cohort study presents the physiological changes in biochemical indices of calcium homeostasis and bone metabolism during pregnancy and lactation INTRODUCTION: We describe...... physiological changes in calcium homeostasis, calcitropic hormones and bone metabolism during pregnancy and lactation. METHODS: We studied 153 women planning pregnancy (n=92 conceived) and 52 non-pregnant, age-matched female controls. Samples were collected prior to pregnancy, once each trimester and 2, 16...

  7. Insulin-like growth factor I enhances proenkephalin synthesis and dopamine. beta. -hydroxylase activity in adrenal chromaffin cells

    Energy Technology Data Exchange (ETDEWEB)

    Wilson, S.P. (Univ. of South Carolina School of Medicine, Columbia (USA))

    1991-01-01

    Insulin-like growth factor I (IGF-I) increased both the contents of proenkephalin derived enkephalin-containing peptides and the activity of dopamine {beta}-hydroxylase in bovine adrenal chromaffin cells. These increases in dopamine {beta}-hydroxylase and enkephalin-containing peptides continued for at least 8 days. The half-maximal IGF-I concentration for these effects was {approximately} 1 nM, with maximal effects observed at 10-30 nM. In contrast, insulin was 1,000-fold less potent. Pretreatment of chromaffin cells with IGF-I increased the rate of ({sup 35}S)proenkephalin synthesis 4-fold compared to untreated cells. Total protein synthesis increased only 1.5-fold under these conditions. These results suggest that IGF-I may be a normal regulator of chromaffin cell function.

  8. Effects of insulin-like growth factor-I on bone metabolism in patients with liver cirrhosis

    International Nuclear Information System (INIS)

    Li Xiaohong; Gao Wenjin; Wang Mingtao; Hu Haiqiang

    2006-01-01

    To study the effects of serum insulin-like growth factor-I (IGF-I) on bone metabolism in liver cirrhosis, 44 patients with hepatic cirrhosis were divided into 3 groups according to disease severity (Child Pugh Score) and 38 healthy subjects served as controls. Serum levels of IGF-I and osteocalcin(BGP) were measured in all patients and controls. Results showed that levels of IGF-I, BGP, and BMD were lower significantly in patients with liver cirrhosis than that in controls. When the condition of cirrhosis more deteriorated, these changes became much lower significantly. Serum levels of BGP and BMD were positively correlated with IGF-I. The decreasing level of IGF-I might be an important factor causing osteoporosis in patients with liver cirrhosis. (authors)

  9. Plasma leptin and insulin-like growth factor I levels during acute exacerbations of chronic obstructive pulmonary disease.

    Science.gov (United States)

    Kythreotis, Prokopis; Kokkini, Ageliki; Avgeropoulou, Stavrina; Hadjioannou, Argyro; Anastasakou, Efgenia; Rasidakis, Antonis; Bakakos, Petros

    2009-04-05

    Recent studies have provided evidence for a link between leptin and tumor necrosis factor-alpha (TNF-alpha). Insulin-like growth factor I (IGF-I) mediates the metabolic effects of growth hormone (GH). The GH axis is believed to be suppressed in chronic obstructive pulmonary disease (COPD). The aim of this study is to find out whether acute exacerbations of COPD are followed by changes in plasma leptin and insulin-like growth factor I (IGF-I) levels and furthermore, whether these changes are related to systemic inflammation. We measured serum leptin, IGF-I, TNF-alpha, interleukin 1 beta (IL-1 beta), interleukin 6 (IL-6) and interleukin 8 (IL-8) levels in 52 COPD patients with acute exacerbation on admission to hospital (Day 1) and two weeks later (Day 15). 25 healthy age-matched subjects served as controls. COPD patients were also divided into two subgroups (29 with chronic bronchitis and 23 with emphysema). Serum leptin and IGF-I were measured by radioimmunoassay and TNF-alpha, IL-1 beta, IL-6 and IL-8 were measured by ELISA. Serum leptin levels were significantly higher and serum IGF-I levels significantly lower in COPD patients on Day 1 than in healthy controls (p leptin and TNF-alpha on Day 1 (r = 0.620, p leptin levels along with decreased IGF-I levels occurred during acute exacerbations of COPD. Compared to chronic bronchitis, patients with emphysema had lower circulating IGF-I levels both at the onset of the exacerbation and two weeks later.

  10. Plasma leptin and insulin-like growth factor I levels during acute exacerbations of chronic obstructive pulmonary disease

    Directory of Open Access Journals (Sweden)

    Rasidakis Antonis

    2009-04-01

    Full Text Available Abstract Background Recent studies have provided evidence for a link between leptin and tumor necrosis factor-alpha (TNF-α. Insulin-like growth factor I (IGF-I mediates the metabolic effects of growth hormone (GH. The GH axis is believed to be suppressed in chronic obstructive pulmonary disease (COPD. The aim of this study is to find out whether acute exacerbations of COPD are followed by changes in plasma leptin and insulin-like growth factor I (IGF-I levels and furthermore, whether these changes are related to systemic inflammation. Methods We measured serum leptin, IGF-I, TNF-α, interleukin 1β (IL-1β, interleukin 6 (IL-6 and interleukin 8 (IL-8 levels in 52 COPD patients with acute exacerbation on admission to hospital (Day 1 and two weeks later (Day 15. 25 healthy age-matched subjects served as controls. COPD patients were also divided into two subgroups (29 with chronic bronchitis and 23 with emphysema. Serum leptin and IGF-I were measured by radioimmunoassay and TNF-α, IL-1β, IL-6 and IL-8 were measured by ELISA. Results Serum leptin levels were significantly higher and serum IGF-I levels significantly lower in COPD patients on Day 1 than in healthy controls (p Conclusion Inappropriately increased circulating leptin levels along with decreased IGF-I levels occured during acute exacerbations of COPD. Compared to chronic bronchitis, patients with emphysema had lower circulating IGF-I levels both at the onset of the exacerbation and two weeks later.

  11. The immune-endocrine loop during aging: role of growth hormone and insulin-like growth factor-I.

    Science.gov (United States)

    Burgess, W; Liu, Q; Zhou, J; Tang, Q; Ozawa, A; VanHoy, R; Arkins, S; Dantzer, R; Kelley, K W

    1999-01-01

    Why a primary lymphoid organ such as the thymus involutes during aging remains a fundamental question in immunology. Aging is associated with a decrease in plasma growth hormone (somatotropin) and IGF-I, and this somatopause of aging suggests a connection between the neuroendocrine and immune systems. Several investigators have demonstrated that treatment with either growth hormone or IGF-I restores architecture of the involuted thymus gland by reversing the loss of immature cortical thymocytes and preventing the decline in thymulin synthesis that occurs in old or GH-deficient animals and humans. The proliferation, differentiation and functions of other components of the immune system, including T and B cells, macrophages and neutrophils, also demonstrate age-associated decrements that can be restored by IGF-I. Knowledge of the mechanism by which cytokines and hormones influence hematopoietic cells is critical to improving the health of aged individuals. Our laboratory has recently demonstrated that IGF-I prevents apoptosis in promyeloid cells, which subsequently permits these cells to differentiate into neutrophils. We also demonstrated that IL-4 acts much like IGF-I to promote survival of promyeloid cells and to activate the enzyme phosphatidylinositol 3'-kinase (PI 3-kinase). However, the receptors for IGF-I and IL-4 are completely different, with the intracellular beta chains of the IGF receptor possessing intrinsic tyrosine kinase activity and the alpha and gammac subunit of the heterodimeric IL-4 receptor utilizing the Janus kinase family of nonreceptor protein kinases to tyrosine phosphorylate downstream targets. Both receptors share many of the components of the PI 3-kinase signal transduction pathway, converging at the level of insulin receptor substrate-1 or insulin receptor subtrate-2 (formally known as 4PS, or IL-4 Phosphorylated Substrate). Our investigations with IGF-I and IL-4 suggest that PI 3-kinase inhibits apoptosis by maintaining high levels of

  12. Absorption of milk-borne insulin-like growth factor-I into portal blood of suckling rats.

    Science.gov (United States)

    Philipps, A F; Dvorák, B; Kling, P J; Grille, J G; Koldovský, O

    2000-08-01

    Insulin-like growth factors (IGFs) are potent mitogens that have been implicated in control of growth and development during the perinatal period. These hormones are also present in biologically significant quantities in mammalian milks. Although one site of action of these IGFs may be at the intestinal level, current information about whether they pass intact into the circulation is conflicting. To test the hypothesis that milk-borne IGFs are absorbed into blood in receptor-active form, suckling rats were given either recombinant human (rh)125I-IGF-I or -II (4 x 10(6) counts per minute [cpm]), and the activity present in portal and cardiac blood was examined at 5, 10, 20, and 30 minutes after ingestion for presence of appropriate molecular weight peptides in these samples. In selected samples, purified radioactive samples were tested for their ability to bind competitively to crude membranes bearing IGF receptors. The results of these studies indicate that rh125I-IGF-I is absorbed in receptor-active form into the portal circulation and that maximal amounts are present 20 to 30 minutes after ingestion. Estimation of the presence of intact hormone was made on the basis of the elution profile of samples when run on gel chromatography as well as reversed-phase high-performance liquid chromatography. Isolated samples from portal blood also bound competitively to placental membranes bearing IGF receptors. In contrast, rh125I-IGF-II could not be demonstrated in receptor-active form in portal blood. Chromatography showed appropriate sized peaks with greater activity in portal than cardiac samples, but competitive binding was not appreciated. It is likely that at least milk-borne IGF-I is absorbed intact and may exert effects on liver and other peripheral tissues. In addition, this study lends further credence to the possibility of an enterohepatic circulation for IGF-I.

  13. Increase in tendon protein synthesis in response to insulin-like growth factor-I is preserved in elderly men

    DEFF Research Database (Denmark)

    Nielsen, Rie Harboe; Holm, Lars; Malmgaard-Clausen, Nikolaj Mølkjær

    2014-01-01

    Insulin-like growth factor-I (IGF-I) is known to be an anabolic factor in tendon, and the systemic levels are reduced with aging. However, it is uncertain how tendon fibroblasts are involved in tendon aging and how aging cells respond to IGF-I. The purpose of this study was to investigate...... the in vivo IGF-I stimulation of tendon protein synthesis in elderly compared with young men. We injected IGF-I in the patellar tendons of young (n = 11, 20-30 yr of age) and old (n = 11, 66-75 yr of age) men, and the acute fractional synthesis rate (FSR) of tendon protein was measured with the stable isotope...... technique and compared with the contralateral side (injected with saline as control). We found that tendons injected with IGF-I had significantly higher protein FSR compared with controls (old group: 0.018 ± 0.015 vs. 0.008 ± 0.008, young group: 0.016 ± 0.009 vs. 0.009 ± 0.006%/h, mean ± SE, P

  14. Cleavage factor I links transcription termination to DNA damage response and genome integrity maintenance in Saccharomyces cerevisiae.

    Directory of Open Access Journals (Sweden)

    Hélène Gaillard

    2014-03-01

    Full Text Available During transcription, the nascent pre-mRNA undergoes a series of processing steps before being exported to the cytoplasm. The 3'-end processing machinery involves different proteins, this function being crucial to cell growth and viability in eukaryotes. Here, we found that the rna14-1, rna15-1, and hrp1-5 alleles of the cleavage factor I (CFI cause sensitivity to UV-light in the absence of global genome repair in Saccharomyces cerevisiae. Unexpectedly, CFI mutants were proficient in UV-lesion repair in a transcribed gene. DNA damage checkpoint activation and RNA polymerase II (RNAPII degradation in response to UV were delayed in CFI-deficient cells, indicating that CFI participates in the DNA damage response (DDR. This is further sustained by the synthetic growth defects observed between rna14-1 and mutants of different repair pathways. Additionally, we found that rna14-1 suffers severe replication progression defects and that a functional G1/S checkpoint becomes essential in avoiding genetic instability in those cells. Thus, CFI function is required to maintain genome integrity and to prevent replication hindrance. These findings reveal a new function for CFI in the DDR and underscore the importance of coordinating transcription termination with replication in the maintenance of genomic stability.

  15. Nuclear Factor I-C promotes proliferation and differentiation of apical papilla-derived human stem cells in vitro

    Energy Technology Data Exchange (ETDEWEB)

    Zhang, Jing [State Key Laboratory of Military Stomatology, Department of Operative Dentistry & Endodontics, School of Stomatology, The Fourth Military Medical University, Xi' an (China); Stomatologic Hospital & College, Anhui Medical University, Key Lab of Oral Diseases Research of Anhui Province, Hefei (China); Wang, Zhihua; Jiang, Yong [State Key Laboratory of Military Stomatology, Department of Operative Dentistry & Endodontics, School of Stomatology, The Fourth Military Medical University, Xi' an (China); Niu, Zhongying [Treatment center of oral diseases, The 306th Hospital of People' s Liberation Army, Beijing (China); Fu, Lei; Luo, Zhirong [State Key Laboratory of Military Stomatology, Department of Operative Dentistry & Endodontics, School of Stomatology, The Fourth Military Medical University, Xi' an (China); Cooper, Paul R.; Smith, Anthony J. [Oral Biology, School of Dentistry, University of Birmingham, B4 6NN (United Kingdom); He, Wenxi, E-mail: hewenxi@fmmu.edu.cn [State Key Laboratory of Military Stomatology, Department of Operative Dentistry & Endodontics, School of Stomatology, The Fourth Military Medical University, Xi' an (China)

    2015-03-15

    The transcription factor Nuclear Factor I-C (NFIC) has been implicated in the regulation of tooth root development, where it may be anticipated to impact on the behavior of stem cells from the apical papilla (SCAPs) and root odontoblast activity. We hypothesized that NFIC may provide an important target for promoting dentin/root regeneration. In the present study, the effects of NFIC on the proliferation and differentiation of SCAPs were investigated. Over-expression of NFIC increased cell proliferation, mineralization nodule formation and alkaline phosphatase (ALP) activity in SCAPs. Furthermore, NFIC up-regulated the mRNA levels of odontogenic-related markers, ALP, osteocalcin and collagen type I as well as dentin sialoprotein protein levels. In contrast, knockdown of NFIC by si-RNA inhibited the mineralization capacity of SCAPs and down-regulated the expression of odontogenic-related markers. In conclusion, the results indicated that upregulation of NFIC activity in SCAPs may promote osteo/odontoblastic differentiation of SCAPs. - Highlights: • NFIC promotes the proliferation of SCAPs in vitro. • NFIC promotes osteo/odontogenic differentiation of SCAPs in vitro. • Knockdown of NFIC inhibits odontogenic differentiation in SCAPs.

  16. Cow milk consumption, insulin-like growth factor-I, and human biology: a life history approach.

    Science.gov (United States)

    Wiley, Andrea S

    2012-01-01

    To assess the life history consequences of cow milk consumption at different stages in early life (prenatal to adolescence), especially with regard to linear growth and age at menarche and the role of insulin-like growth factor I (IGF-I) in mediating a relationship among milk, growth and development, and long-term biological outcomes. United States National Health and Nutrition Examination Survey (NHANES) data from 1999 to 2004 and review of existing literature. The literature tends to support milk's role in enhancing growth early in life (prior to age 5 years), but there is less support for this relationship during middle childhood. Milk has been associated with early menarche and with acceleration of linear growth in adolescence. NHANES data show a positive relationship between milk intake and linear growth in early childhood and adolescence, but not middle childhood, a period of relatively slow growth. IGF-I is a candidate bioactive molecule linking milk consumption to more rapid growth and development, although the mechanism by which it may exert such effects is unknown. Routine milk consumption is an evolutionarily novel dietary behavior that has the potential to alter human life history parameters, especially vis-à-vis linear growth, which in turn may have negative long-term biological consequences. Copyright © 2011 Wiley Periodicals, Inc.

  17. Growth and Growth hormone - Insulin Like Growth Factor -I (GH-IGF-I) Axis in Chronic Anemias.

    Science.gov (United States)

    Soliman, Ashraf T; De Sanctis, Vincenzo; Yassin, Mohamed; Adel, Ashraf

    2017-04-28

    Anaemia is a global public health problem affecting both developing and developed countries with major consequences for human health as well as social and economic development. It occurs at all stages of the life cycle, but is more prevalent in pregnant women and young children. Iron deficiency anaemia (IDA) was considered to be among the most important contributing factors to the global burden of disease. Prolonged and/or chronic anemia has a negative effect on linear growth especially during the rapid phases (infancy and puberty). Additionally infants with chronic IDA have delayed cognitive, motor, and affective development that may be long-lasting. In view of the significant impact of chronic anemias on growth, pediatricians endocrinologists and hematologists should advocate primary prevention and screening for growth disturbance in these forms of anemias. The extent of the negative effect of different forms of chronic anemias on linear growth and its possible reversibilty is addressed in this review. The possible mechanisms that may impair growth in the different forms of anemias are addressed with special attention to their effect on the growth hormone (GH) - insulin like growth factor -I (IGF-I).

  18. Adult and near-adult height in patients with severe insulin-like growth factor-I deficiency after long-term therapy with recombinant human insulin-like growth factor-I.

    Science.gov (United States)

    Backeljauw, Philippe F; Kuntze, Joyce; Frane, James; Calikoglu, Ali S; Chernausek, Steven D

    2013-01-01

    Treatment with recombinant human insulin-like growth factor-I (IGF-I) stimulates linear growth in children with severe IGF-I deficiency (IGFD). To evaluate the efficacy and safety of treatment with IGF-I in patients with severe IGFD treated until adult or near-adult height. Twenty-one children with severe IGFD were treated until adult or near-adult height under a predominantly open-label design. All patients were naive to IGF-I. Recombinant human IGF-I was administered subcutaneously in doses between 60 and 120 µg/kg twice daily. Nine patients received additional therapy with gonadotropin- releasing hormone (GnRH) analog for a mean period of 2.9 ± 1.8 years. Mean duration of treatment was 10.0 years. Mean height velocity increased from 3.1 cm/year prior to treatment to 7.4 cm/year during the first year of treatment. Height velocities during the subsequent years were lower, but remained above baseline for up to 12 years. Cumulative mean Δ height SD score at (near) adult height was +2. The observed mean gain in height was 13.4 cm more than had been expected without treatment. The adult height achieved by the patients also treated with GnRH analog was not different from those who received IGF-I therapy alone. There were no new safety signals identified in these patients, a subset of those previously reported. Long-term therapy with IGF-I improves adult height of patients with severe IGFD. Most patients did not bring their heights into the normal adult range. Copyright © 2013 S. Karger AG, Basel.

  19. Correlations of IGF-1R and COX-2 Expressions with Ras and BRAF Genetic Mutations, Clinicopathological Features and Prognosis of Colorectal Cancer Patients.

    Science.gov (United States)

    Jin, Mei; Long, Zi-Wen; Yang, Jing; Lin, Xiang

    2018-01-01

    This case-control study aims to investigate the correlations of insulin-like growth factor receptor 1 (IGF-1R) and cyclooxygenase 2 (COX-2) expressions with Ras and BRAF genetic mutations, clinicopathological features and prognosis of colorectal cancer (CRC) patients. A total of 213 CRC patients (case group) and 200 healthy individuals (control group) were selected from our hospital. Ras (K-Ras/N-Ras) and BRAF genetic mutations were detected by direct sequencing. The positive expression rates of IGF-IR and COX-2 in CRC and normal tissues were detected using immunohistochemistry. RT-qPCR and Western blotting were applied to detect the mRNA and protein expressions of IGF-IR and COX-2 in CRC tissues and normal tissues. Total mutation rate of N-Ras, BRAF and K-Ras in case group were 5.2%, 12.2% and 47.4%, respectively. The expressions of IGF-IR and COX-2 were higher in CRC tissues with Ras and BRAF mutations than in those without. CRC tissues with Ras mutation showed higher COX-2 expression than those with BRAF mutation. IGF-IR and COX-2 expressions were correlated to infiltration degree, lymphatic metastasis (in CRC tissues with and without Ras and BRAF mutations), and Dukes stages (only in CRC tissues with Ras and BRAF mutations). CRC patients with negative expressions of IGF-IR and COX-2 had significantly higher accumulative survival rate and longer mean survival duration than those with positive expressions of IGF-IR and COX-2. These findings indicate that IGF-1R and COX-2 expressions may be associated with Ras and BRAF genetic mutations, clinicopathological feature and prognosis of CRC patients.

  20. The Mechanism of Action of the Histone Deacetylase Inhibitor Vorinostat Involves Interaction with the Insulin-Like Growth Factor Signaling Pathway

    Science.gov (United States)

    Sarfstein, Rive; Bruchim, Ilan; Fishman, Ami; Werner, Haim

    2011-01-01

    A correlation between components of the insulin-like growth factor (IGF) system and endometrial cancer risk has been shown in recent studies. The antitumor action of vorinostat, a histone deacetylase inhibitor, involves changes in the expression of specific genes via acetylation of histones and transcription factors. The aim of this study was to establish whether vorinostat can modify the expression of specific genes related to the IGF-I receptor (IGF-IR) signaling pathway and revert the transformed phenotype. Human endometrioid (Type I, Ishikawa) and uterine serous papillary (Type II, USPC-2) endometrial cancer cell lines were treated with vorinostat in the presence or absence of IGF-I. Vorinostat increased IGF-IR phosphorylation, produced acetylation of histone H3, up-regulated pTEN and p21 expression, and reduced p53 and cyclin D1 levels in Ishikawa cells. Vorinostat up-regulated IGF-IR and p21 expression, produced acetylation of histone H3, and down-regulated the expression of total AKT, pTEN and cyclin D1 in USPC-2 cells. Of interest, IGF-IR activation was associated with a major elevation in IGF-IR promoter activity. In addition, vorinostat treatment induced apoptosis in both cell lines and abolished the anti-apoptotic activity of IGF-I both in the absence or presence of a humanized monoclonal IGF-IR antibody, MK-0646. Finally, vorinostat treatment led to a significant decrease in proliferation and colony forming capability in both cell lines. In summary, our studies demonstrate that vorinostat exhibits a potent apoptotic and anti-proliferative effect in both Type I and II endometrial cancer cells, thus suggesting that endometrial cancer may be therapeutically targeted by vorinostat. PMID:21931726

  1. The mechanism of action of the histone deacetylase inhibitor vorinostat involves interaction with the insulin-like growth factor signaling pathway.

    Directory of Open Access Journals (Sweden)

    Rive Sarfstein

    Full Text Available A correlation between components of the insulin-like growth factor (IGF system and endometrial cancer risk has been shown in recent studies. The antitumor action of vorinostat, a histone deacetylase inhibitor, involves changes in the expression of specific genes via acetylation of histones and transcription factors. The aim of this study was to establish whether vorinostat can modify the expression of specific genes related to the IGF-I receptor (IGF-IR signaling pathway and revert the transformed phenotype. Human endometrioid (Type I, Ishikawa and uterine serous papillary (Type II, USPC-2 endometrial cancer cell lines were treated with vorinostat in the presence or absence of IGF-I. Vorinostat increased IGF-IR phosphorylation, produced acetylation of histone H3, up-regulated pTEN and p21 expression, and reduced p53 and cyclin D1 levels in Ishikawa cells. Vorinostat up-regulated IGF-IR and p21 expression, produced acetylation of histone H3, and down-regulated the expression of total AKT, pTEN and cyclin D1 in USPC-2 cells. Of interest, IGF-IR activation was associated with a major elevation in IGF-IR promoter activity. In addition, vorinostat treatment induced apoptosis in both cell lines and abolished the anti-apoptotic activity of IGF-I both in the absence or presence of a humanized monoclonal IGF-IR antibody, MK-0646. Finally, vorinostat treatment led to a significant decrease in proliferation and colony forming capability in both cell lines. In summary, our studies demonstrate that vorinostat exhibits a potent apoptotic and anti-proliferative effect in both Type I and II endometrial cancer cells, thus suggesting that endometrial cancer may be therapeutically targeted by vorinostat.

  2. Optimization of IGF-1R SPECT/CT Imaging Using In-111-Labeled F(ab ')(2) and Fab Fragments of Article the Monoclonal Antibody R1507

    NARCIS (Netherlands)

    Heskamp, S.; Laarhoven, H.W.M. van; Molkenboer-Kuenen, J.D.M.; Bouwman, W.H.; van der Graaf, W.T.; Oyen, W.J.G.; Boerman, O.C.

    2012-01-01

    The insulin-like growth factor 1 receptor (IGF-1R) is a potential new target for the treatment of breast cancer. Patients with breast cancer lesions that express IGF-1R may benefit from treatment with anti-IGF-IR antibodies. IGF-1R expression can be visualized using radiolabeled R1507, a monoclonal

  3. Serum insulin-like growth factor-I levels are associated with improved white matter recovery after traumatic brain injury.

    Science.gov (United States)

    Feeney, Claire; Sharp, David J; Hellyer, Peter J; Jolly, Amy E; Cole, James H; Scott, Gregory; Baxter, David; Jilka, Sagar; Ross, Ewan; Ham, Timothy E; Jenkins, Peter O; Li, Lucia M; Gorgoraptis, Nikos; Midwinter, Mark; Goldstone, Anthony P

    2017-07-01

    Traumatic brain injury (TBI) is a common disabling condition with limited treatment options. Diffusion tensor imaging measures recovery of axonal injury in white matter (WM) tracts after TBI. Growth hormone deficiency (GHD) after TBI may impair axonal and neuropsychological recovery, and serum insulin-like growth factor-I (IGF-I) may mediate this effect. We conducted a longitudinal study to determine the effects of baseline serum IGF-I concentrations on WM tract and neuropsychological recovery after TBI. Thirty-nine adults after TBI (84.6% male, median age = 30.5 years, 87.2% moderate-severe, median time since TBI = 16.3 months, n = 4 with GHD) were scanned twice, 13.3 months (range = 12.1-14.9) apart, and 35 healthy controls were scanned once. Symptom and quality of life questionnaires and cognitive assessments were completed at both visits (n = 33). Our main outcome measure was fractional anisotropy (FA), a measure of WM tract integrity, in a priori regions of interest: splenium of corpus callosum (SPCC) and posterior limb of internal capsule (PLIC). At baseline, FA was reduced in many WM tracts including SPCC and PLIC following TBI compared to controls, indicating axonal injury, with longitudinal increases indicating axonal recovery. There was a significantly greater increase in SPCC FA over time in patients with serum IGF-I above versus below the median for age. Only the higher IGF-I group had significant improvements in immediate verbal memory recall over time. WM recovery and memory improvements after TBI were greater in patients with higher serum IGF-I at baseline. These findings suggest that the growth hormone/IGF-I system may be a potential therapeutic target following TBI. Ann Neurol 2017;82:30-43. © 2017 The Authors Annals of Neurology published by Wiley Periodicals, Inc. on behalf of American Neurological Association.

  4. Effects of green tea polyphenols, insulin-like growth factor I and glucose on developmental competence of bovine oocytes

    Directory of Open Access Journals (Sweden)

    Zhengguang Wang

    2012-12-01

    Full Text Available The present study examined the effects of green tea polyphenols (GTP, insulin-like growth factor-I (IGF-I and glucose on oocyte in vitro maturation, subsequent embryo development and blastocyst quality in bovine. Cumulus-oocyte complexes (COC were aspirated from the ovaries and cultured in synthetic oviduct fluid supplemented with MEM amino acids (SOFaa media supplemented with one of the following supplements: GTP (0, 10, 15 and 20 µM, IGF-I (0, 50, 100 and 150 ng/mL or glucose (0, 1.5, 5.6 and 20 mM for 24 h. The results showed that oocytes cultured in media supplemented with 15 µM GTP, 100 ng/mL IGF-I and 5.6 mM glucose, in separate experiments, have higher cleavage and blastocyst rates compared with oocytes cultured in media without or with other concentration of GTP, IGF-I and glucose. Then these three substances with the concentration above were added together into SOFaa media and constituted a modified medium (Modified SOFaa. The COC were cultured in control SOFaa media and modified SOFaa media, respectively. The results showed that modified SOFaa media increased the intracellular glutathione concentration of matured oocytes, blastocyst rates and total cell numbers and cell numbers of inner cell mass per blastocyst compared with the control. Supplementing of GTP, IGF-I and glucose synchronously to maturation media can increase the intracellular GSH concentration of oocytes after in vitro maturation, and improve the embryo development and blastocyst quality in bovine.

  5. Effect of fat supplementation on leptin, insulin-like growth factor I, growth hormone, and insulin in cattle.

    Science.gov (United States)

    Becú-Villalobos, Damasia; García-Tornadú, Isabel; Shroeder, Guillermo; Salado, Eloy E; Gagliostro, Gerardo; Delavaud, Carole; Chilliard, Yves; Lacau-Mengido, Isabel M

    2007-07-01

    We investigated the effect of fat supplementation on plasma levels of hormones related to metabolism, with special attention to leptin, in cows in early lactation and in feedlot steers. In experiment 1, 34 lactating cows received no fat or else 0.5 or 1.0 kg of partially hydrogenated oil per day in addition to their basal diet from day 20 before the expected calving date to day 70 postpartum. In experiment 2, part of the corn in the basal concentrate was replaced with 0.7 kg of the same oil such that the diets were isocaloric; 18 cows received the fat-substituted diet and 18 a control diet from day 20 before the expected calving date to day 75 postpartum. In experiment 3, calcium salts of fatty acids were added to the basal diet of 14 feedlot steers for 80 d; another 14 steers received a control diet. The basal plasma levels of leptin were higher in the cows than in the steers. Dietary fat supplementation did not affect the leptin levels in the lactating cows but lowered the levels in the feedlot steers despite greater energy intake and body fatness (body weight) in the steers receiving the supplement than in those receiving the control diet. The levels of insulin-like growth factor I and insulin were decreased with dietary fat supplementation in the lactating cows but were unaffected in the steers, suggesting that responses to fat ingestion depend on the physiological state of the animal, including age and sex. Finally, no effects of supplementary fat on the level of growth hormone were demonstrated in any of the models.

  6. Regulation of REDD1 by Insulin-like Growth Factor-I in Skeletal Muscle and Myotubes

    Science.gov (United States)

    Frost, Robert A.; Huber, Danuta; Pruznak, Anne; Lang, Charles H.

    2012-01-01

    Insulin-like growth factor-I (IGF-I) is a major anabolic hormone for skeletal muscle and a potent stimulus for protein synthesis and translation initiation. Recent studies suggest that translation can be inhibited by over expression of the mammalian target of rapamycin (mTOR) repressor REDD1. The purpose of the present study was to determine whether IGF-I alters the expression of REDD1 and whether this is associated with a concomitant change in protein synthesis in vitro. Subcutaneous injection of IGF-I or intravenous delivery of insulin for 3–4 h increased REDD1 mRNA in skeletal muscle 7- to10-fold. A 3-fold increase in REDD1 was observed when C2C12 myotubes were treated with IGF-I. REDD1 protein continued to be expressed for up to 24 h after addition of IGF-I to cells. Withdrawal of IGF-I from myotubes lead to a rapid loss of REDD1 protein content. IGF-I-induced REDD1 mRNA and protein expression were prevented by inhibitors of transcription and translation. IGF-I had an additive effect with dexamethasone (Dex) on REDD1 protein content in myotubes. The PI3K inhibitor LY294002 blocked IGF-I but not Dex induced REDD1. IGF-I also stimulated REDD1 promoter activity. Although REDD1 protein was elevated 5–6 h after addition of IGF-I to myotubes, protein synthesis measured during this 1 h window was paradoxically greater in myotubes expressing more REDD1. In contrast to the IGF-I induced increase in REDD1 mRNA, REDD2 mRNA was decreased by IGF-I. We conclude that IGF-I stimulates REDD1 expression in skeletal muscle and myotubes but under these conditions the REDD1 response is not sufficient to repress protein synthesis. PMID:19795384

  7. Determination of insulin-like growth factor-I reference values using an immunoradiometric assay in a Brazilian adult population.

    Science.gov (United States)

    Leite, Denise B; Meirelles, Ricardo M R; Mandarim-De-Lacerda, Carlos A; Matos, Haroldo J; Santos-Filho, Sebastião D; Bernardo-Filho, Mario

    2012-01-01

    Serum levels of total insulin-like growth factor I (IGF-I) reflect endogenous growth hormone (GH) secretion in healthy adults, which makes it a good diagnostic marker for screening of GH-related disorders. Studies also have supported a possible relation between IGF-I levels and the risk and prognostic for some malignancies, besides a relation between IGF-I levels and mortality. As the determination of the IGF-I normal values for local populations is strongly desired, the aim of this investigation was to determine reference values for IGF-I using an immunoradiometric assay (IRMA) in an adult Brazilian population of Rio de Janeiro city, since there is no other study using this methodology in Brazilian population, and that this method is widely used in Brazil and worldwide. The study included samples of blood taken from 484 healthy subjects (251 men and 233 women) aged 18-70. The subjects agreed with this study, approved by the Ethical Committee of the Instituto Estadual de Hematologia Arthur de Siqueira Cavalcanti, Rio de Janeiro, Brazil. The samples were analyzed using a Diagnostic System Laboratories kit. For data analysis, age- and sex-specific figures were fitted after transformation of IGF-I values. In adulthood, a slow age-dependent decrease was found. There was no significant difference in IGF-I values between men and women. This study established age-specific IGF-I reference values, for a healthy Brazilian adult population, determined by a widely IGF-I, IRMA used currently in Brazil.

  8. Insulin-like growth factor-I gene therapy reverses morphologic changes and reduces hyperprolactinemia in experimental rat prolactinomas

    Directory of Open Access Journals (Sweden)

    Bracamonte Maria I

    2008-01-01

    Full Text Available Abstract Background The implementation of gene therapy for the treatment of pituitary tumors emerges as a promising complement to surgery and may have distinct advantages over radiotherapy for this type of tumors. Up to now, suicide gene therapy has been the main experimental approach explored to treat experimental pituitary tumors. In the present study we assessed the effectiveness of insulin-like growth factor I (IGF-I gene therapy for the treatment of estrogen-induced prolactinomas in rats. Results Female Sprague Dawley rats were subcutaneously implanted with silastic capsules filled with 17-β estradiol (E2 in order to induce pituitary prolactinomas. Blood samples were taken at regular intervals in order to measure serum prolactin (PRL. As expected, serum PRL increased progressively and 23 days after implanting the E2 capsules (Experimental day 0, circulating PRL had undergone a 3–4 fold increase. On Experimental day 0 part of the E2-implanted animals received a bilateral intrapituitary injection of either an adenoviral vector expressing the gene for rat IGF-I (RAd-IGFI, or a vector (RAd-GFP expressing the gene for green fluorescent protein (GFP. Seven days post vector injection all animals were sacrificed and their pituitaries morphometrically analyzed to evaluate changes in the lactotroph population. RAd-IGFI but not RAd-GFP, induced a significant fall in serum PRL. Furthermore, RAd-IGFI but not RAd-GFP significantly reversed the increase in lactotroph size (CS and volume density (VD induced by E2 treatment. Conclusion We conclude that IGF-I gene therapy constitutes a potentially useful intervention for the treatment of prolactinomas and that bioactive peptide gene delivery may open novel therapeutic avenues for the treatment of pituitary tumors.

  9. Effects of insulin-like growth factor-I, insulin, and leucine on protein turnover and pathways that regulate ubiquitin ligase expression in rainbow trout primary myocytes

    Science.gov (United States)

    The effects of insulin-like growth factor-I (IGF-I), insulin, and leucine on protein turnover and pathways that regulate proteolytic gene expression and protein polyubiquitination were investigated in primary cultures of four day old rainbow trout myocytes. Supplementing media with 100 nM IGF-I inc...

  10. The stimulatory effect of growth hormone, prolactin, and placental lactogen on beta-cell proliferation is not mediated by insulin-like growth factor-I

    DEFF Research Database (Denmark)

    Billestrup, N; Nielsen, Jens Høiriis

    1991-01-01

    The effects of GH, PRL, and placental lactogen (PL) on the proliferation of pancreatic beta-cells in vitro were studied as well as the possible effect of insulin-like growth factor-I (IGF-I) in mediating this effect. Proliferating beta-cells were identified by staining with a monoclonal antibody ...

  11. 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

  12. Systemic treatment with epidermal growth factor but not insulin-like growth factor I decreases the involution of the prostate in castrated rats

    DEFF Research Database (Denmark)

    Tørring, N; Vinter-Jensen, L; 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...

  13. Effects of octreotide on insulin-like growth factor I and metabolic indices in growth hormone-treated growth hormone-deficient patients

    DEFF Research Database (Denmark)

    Laursen, Torben; Jørgensen, Jens Otto Lunde; Ørskov, Hans

    1993-01-01

    Abstract Animals studies have demonstrated that in addition to inhibiting growth hormone (GH) secretion octreotide inhibits in a direct manner hepatic or peripheral insulin-like growth factor I (IGF-I) generation. To test this hypothesis in humans we studied ten GH-deficient patients with frequent...

  14. Characteristics and reference ranges of Insulin-Like Growth Factor-I measured with a commercially available immunoassay in 724 healthy adult Caucasians

    DEFF Research Database (Denmark)

    Andreassen, Mikkel; Nielsen, Kaspar; Raymond, Ilan

    2009-01-01

    BACKGROUND AND OBJECTIVE: Measurements of Insulin-Like Growth Factor-I (IGF-I) play a pivotal role in the evaluation of the growth hormone-IGF-I axis. Due to assay variation IGF-I reference ranges are assay specific. We provide serum IGF-I reference ranges for adult men and women obtained...

  15. Relationship between Insulin-Like Growth Factor I Levels, Early Insulin Treatment, and Clinical Outcomes of Very Low Birth Weight Infants

    NARCIS (Netherlands)

    Beardsall, K.; Vanhaesebrouck, S.; Frystyk, J.; Ogilvy-Stuart, A.L.; Vanhole, C.; van Weissenbruch, M.M.; Midgley, P.; Thio, M.; Cornette, L.; Gill, B.; Ossuetta, I.; Iglesias, I.; Theyskens, C.; de Jong, M.; Ahluwalia, J.S.; de Zegher, F.; Dunger, D.B.

    2014-01-01

    Objectives Insulin regulates the secretion of insulin-like growth factor I (IGF-I) in the newborn, and low levels of IGF-I have been linked to neonatal morbidity. As part of the Neonatal Insulin Replacement Therapy in Europe Trial, we investigated the impact of early insulin treatment on IGF-I

  16. The effects of physical activity and fitness in adolescence on cognition in adulthood and the role of insulin-like growth factor I

    NARCIS (Netherlands)

    Ferro, D.A.; Deijen, J.B.; Koppes, L.L.; Mechelen, W. van; Twisk, J.W.; Drent, M.L.

    2016-01-01

    Background: Physical activity and fitness in adolescence may improve cognition in adulthood by increasing insulin-like growth factor I (IGF-I). Methods: As part of the Amsterdam Growth and Health Longitudinal Study, following subjects from age 13 to 42 years, physical activity and fitness of 303

  17. NEUROPROTECTIVE EFFICACY OF SUBCUTANEOUS INSULIN-LIKE GROWTH FACTOR-I ADMINISTRATION IN NORMOTENSIVE AND HYPERTENSIVE RATS WITH AN ISCHEMIC STROKE

    NARCIS (Netherlands)

    de Geyter, D.; Stoop, W.; Sarre, S.; de Keyser, J.; Kooijman, R.

    2013-01-01

    The aim of this study was to test the insulin-like growth factor-I (IGF-I) as a neuroprotective agent in a rat model for ischemic stroke and to compare its neuroprotective effects in conscious normotensive and spontaneously hypertensive rats. The effects of subcutaneous IGF-I injection were

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

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    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. Targeting both IGF-1R and mTOR synergistically inhibits growth of renal cell carcinoma in vitro

    International Nuclear Information System (INIS)

    Cardillo, Thomas M; Trisal, Preeti; Arrojo, Roberto; Goldenberg, David M; Chang, Chien-Hsing

    2013-01-01

    Advanced or metastatic renal cell carcinoma (RCC) has a poor prognosis, because it is relatively resistant to conventional chemotherapy or radiotherapy. Treatments with human interferon-α2b alone or in combination with mammalian target of rapamycin (mTOR) inhibitors have led to only a modest improvement in clinical outcome. One observation made with mTOR inhibitors is that carcinomas can overcome these inhibitory effects by activating the insulin-like growth factor-I (IGF-I) signaling pathway. Clinically, there is an association of IGF-I receptor (IGF-IR) expression in RCC and poor long-term patient survival. We have developed a humanized anti-IGF-IR monoclonal antibody, hR1, which binds to RCC, resulting in effective down-regulation of IGF-IR and moderate inhibition of cell proliferation in vitro. In this work, we evaluate the anti-tumor activity of two novel IGF-1R-targeting agents against renal cell carcinoma given alone or in combination with an mTOR inhibitor. hR1 was linked by the DOCK-AND-LOCK™ (DNL™) method to four Fabs of hR1, generating Hex-hR1, or to four molecules of interferon-α2b, generating 1R-2b. Eight human RCC cell lines were screened for IGF-1R expression and sensitivity to treatment with hR1 in vitro. Synergy with an mTOR inhibitor, temsirolimus, was tested in a cell line (ACHN) with low sensitivity to hR1. Hex-hR1 induced the down-regulation of IGF-IR at 10-fold lower concentrations compared to the parental hR1. Sensitivity to growth inhibition mediated by hR1 and Hex-hR1 treatments correlated with IGF-1R expression (higher expression was more sensitive). The potency of 1R-2b to inhibit the in vitro growth of RCC was also demonstrated in two human cell lines, ACHN and 786-O, with EC 50 –values of 63 and 48 pM, respectively. When combined with temsirolimus, a synergistic growth-inhibition with hR1, Hex-hR1, and 1R-2b was observed in ACHN cells at concentrations as low as 10 nM for hR1, 1 nM for Hex-hR1, and 2.6 nM for 1R-2b. Both Hex-hR1

  20. Effects of prednisolone on serum and tissue fluid IGF-I receptor activation and post-receptor signaling in humans

    DEFF Research Database (Denmark)

    Ramshanker, Nilani; Aagaard, Maiken; Hjortebjerg, Rikke

    2017-01-01

    Context: Short-term glucocorticoid exposure increases serum IGF-I concentrations, but antagonizes IGF-I tissue signaling. The underlying mechanisms remain unknown. Objective: To identify at which levels glucocorticoid inhibits IGF-I signaling. Design and methods: Nineteen healthy males received...... prednisolone (37.5 mg daily) and placebo for 5 days in a randomized, double-blinded, placebo-controlled cross-over study. Serum was collected on day 1, 3 and 5, abdominal skin suction blister fluid (SBF; ≈interstitial fluid) on day 5 (n=9) together with muscle biopsies (n=19). The ability of serum and SBF......-A (PAPP-A). Concomitantly, prednisolone increased SBF levels of stanniocalcin-2 (STC2) (P=0.02) when compared to serum. STC2 blocks PAPP-A from cleaving IGFBP-4. Finally, prednisolone suppressed post-IGF-IR signaling pathways at the level of IRS-1(P

  1. Insulin-like growth factor I is required for the anabolic actions of parathyroid hormone on mouse bone

    Science.gov (United States)

    Bikle, Daniel D.; Sakata, Takeshi; Leary, Colin; Elalieh, Hashem; Ginzinger, David; Rosen, Clifford J.; Beamer, Wesley; Majumdar, Sharmila; Halloran, Bernard P.

    2002-01-01

    Parathyroid hormone (PTH) is a potent anabolic agent for bone, but the mechanism(s) by which it works remains imperfectly understood. Previous studies have indicated that PTH stimulates insulin-like growth factor (IGF) I production, but it remains uncertain whether IGF-I mediates some or all of the skeletal actions of PTH. To address this question, we examined the skeletal response to PTH in IGF-I-deficient (knockout [k/o]) mice. These mice and their normal littermates (NLMs) were given daily injections of PTH (80 microg/kg) or vehicle for 2 weeks after which their tibias were examined for fat-free weight (FFW), bone mineral content, bone structure, and bone formation rate (BFR), and their femurs were assessed for mRNA levels of osteoblast differentiation markers. In wild-type mice, PTH increased FFW, periosteal BFR, and cortical thickness (C.Th) of the proximal tibia while reducing trabecular bone volume (BV); these responses were not seen in the k/o mice. The k/o mice had normal mRNA levels of the PTH receptor and increased mRNA levels of the IGF-I receptor but markedly reduced basal mRNA levels of the osteoblast markers. Surprisingly, these mRNAs in the k/o bones increased several-fold more in response to PTH than the mRNAs in the bones from their wild-type littermates. These results indicate that IGF-I is required for the anabolic actions of PTH on bone formation, but the defect lies distal to the initial response of the osteoblast to PTH.

  2. Glutamate receptors

    DEFF Research Database (Denmark)

    Kristensen, Anders S; Geballe, Matthew T; Snyder, James P

    2006-01-01

    Fast excitatory synaptic transmission in the CNS relies almost entirely on the neurotransmitter glutamate and its family of ion channel receptors. An appreciation of the coupling between agonist binding and channel opening has advanced rapidly during the past five years, largely as a result of ne...

  3. Infection of growing swine with porcine reproductive and respiratory syndrome virus and Mycoplasma hyopneumoniae — Effects on growth, serum metabolites, and insulin-like growth factor-I.

    OpenAIRE

    Roberts, N. Elizabeth; Almond, Glen W.

    2003-01-01

    This study evaluated the influence of concomitant infections with porcine reproductive and respiratory syndrome virus (PRRSV) and Mycoplasma hyopneumoniae on growth performance, serum metabolite concentrations, and serum insulin-like growth factor-I (IGF-I) in growing pigs. Twenty-two barrows (10 weeks of age) were treated with either an intranasal administration of PRRSV and an intratracheal infusion of M. hyopneumoniae (treatment; n = 8) or a sham inoculation with medium (sham; n = 8), or w...

  4. Early-age feed restriction affects viability and gene expression of satellite cells isolated from the gastrocnemius muscle of broiler chicks

    Directory of Open Access Journals (Sweden)

    Li Yue

    2012-11-01

    Full Text Available Abstract Background Muscle growth depends on the fusion of proliferate satellite cells to existing myofibers. We reported previously that 0–14 day intermittent feeding led to persistent retardation in myofiber hypertrophy. However, how satellite cells respond to such nutritional insult has not been adequately elucidated. Results One-day-old broiler chicks were allocated to control (Con, ad libitum feeding, intermittent feeding (IF, feed provided on alternate days and re-feeding (RF, 2 days ad libitum feeding after 12 days of intermittent feeding groups. Chickens were killed on Day 15 and satellite cells were isolated. When cultured, satellite cells from the IF group demonstrated significant retardation in proliferation and differentiation potential, while RF partly restored the proliferation rate and differentiation potential of the satellite cells. Significant up-regulation of insulin like growth factor I receptor (IGF-IR (P0.05 and thyroid hormone receptor α (TRα (P0.05, and down-regulation of growth hormone receptor (GHR (P0.01 and IGF-I (P0.01 mRNA expression was observed in freshly isolated IF satellite cells when compared with Con cells. In RF cells, the mRNA expression of IGF-I was higher (P0.05 and of TRα was lower (P0.01 than in IF cells, suggesting that RF restored the mRNA expression of TRα and IGF-I, but not of GHR and IGF-IR. The Bax/Bcl-2 ratio tended to increase in the IF group, which was reversed in the RF group (P0.05, indicating that RF reduced the pro-apoptotic influence of IF. Moreover, no significant effect of T3 was detected on cell survival in IF cells compared with Con (PP0.05 cells. Conclusions These data suggest that early-age feed restriction inhibits the proliferation and differentiation of satellite cells, induces changes in mRNA expression of the GH/IGF-I and thyroid hormone receptors in satellite cells, as well as blunted sensitivity of satellite cells to T3, and that RF partially reverses these effects. Thus

  5. Inhibition of Insulin like growth factor-I expression by chromatographic fraction of Polygonum hydropiper root reduces implantation preference in rat

    Directory of Open Access Journals (Sweden)

    Pranjiv Goswami

    2014-03-01

    Major conclusions: The root of P. hydropiper contains compound(s with capability to modulate transcription and expression of IGF-I in rat uterus during early gestation. Down regulation of IGF-I results suggests that the phytocompound(s work through the ovarian steroid receptor(s resulting in an inhibition of decidual cell reaction and implantation.

  6. Systemic treatment with epidermal growth factor but not insulin-like growth factor I decreases the involution of the prostate in castrated rats

    DEFF Research Database (Denmark)

    Tørring, N; Vinter-Jensen, L; 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...

  7. Insulin-like growth factor I and glucagon-like peptide-2 responses to fasting followed by controlled or ad libitum refeeding in rats

    DEFF Research Database (Denmark)

    Nelson, David W; Murali, Sangita G; Liu, Xiaowen

    2008-01-01

    Luminal nutrients stimulate structural and functional regeneration in the intestine through mechanisms thought to involve insulin-like growth factor I (IGF-I) and glucagon-like peptide-2 (GLP-2). We investigated the relationship between IGF-I and GLP-2 responses and mucosal growth in rats fasted...... for 48 h and then refed for 2 or 4 days by continuous intravenous or intragastric infusion or ad libitum feeding. Fasting induced significant decreases in body weight, plasma concentrations of IGF-I and bioactive GLP-2, jejunal mucosal cellularity (mass, protein, DNA, and villus height), IGF-I m...

  8. Insulin-like growth factor I treatment reduces demyelination and up-regulates gene expression of myelin-related proteins in experimental autoimmune encephalomyelitis.

    OpenAIRE

    Yao, D L; Liu, X; Hudson, L D; Webster, H D

    1995-01-01

    To compare effects of insulin-like growth factor I (IGF-I) and placebo treatment on lesions that resemble those seen during active demyelination in multiple sclerosis, we induced experimental autoimmune encephalomyelitis in Lewis rats with an emulsion containing guinea pig spinal cord and Freund's adjuvant. On day 12-13, pairs of rats with the same degree of weakness were given either IGF-I or placebo intravenously twice daily for 8 days. After 8 days of placebo or IGF-I (200 micrograms/day o...

  9. The Supportive Role of Insulin-Like Growth Factor-I in the Differentiation of Murine Mesenchymal Stem Cells into Corneal-Like Cells

    Czech Academy of Sciences Publication Activity Database

    Trošan, Peter; Javorková, Eliška; Zajícová, Alena; Hájková, Michaela; Heřmánková, Barbora; Kössl, Jan; Holáň, Vladimír

    2016-01-01

    Roč. 7, č. 17 (2016), s. 23156-23169 ISSN 1547-3287 R&D Projects: GA ČR(CZ) GA14-12580S; GA MŠk(CZ) ED1.1.00/02.0109; GA MŠk(CZ) LO1309; GA MŠk(CZ) LO1508 Institutional support: RVO:68378041 Keywords : mesenchymal stem cells * corneal-like cells * insulin -like growth factor-I * differentiation Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 3.562, year: 2016

  10. Insulin-like growth factor-II (IGF II) receptor from rat brain is of lower apparent molecular weight than the IGF II receptor from rat liver

    International Nuclear Information System (INIS)

    McElduff, A.; Poronnik, P.; Baxter, R.C.

    1987-01-01

    The binding subunits of the insulin and insulin-like growth factor-I (IGF I) receptors from rat brain are of lower molecular weight than the corresponding receptor in rat liver, possibly due to variations in sialic acid content. We have compared the IGF II receptor from rat brain and rat liver. The brain receptor is of smaller apparent mol wt (about 10 K) on sodium dodecyl sulfate polyacrylamide gel electrophoresis. This size difference is independent of ligand binding as it persists in iodinated and specifically immunoprecipitated receptors. From studies of wheat germ agglutinin binding and the effect of neuraminidase on receptor mobility, we conclude that this difference is not simply due to variations in sialic acid content. Treatment with endoglycosidase F results in reduction in the molecular size of both liver and brain receptors and after this treatment the aglycoreceptors are of similar size. We conclude that in rat brain tissue the IGF II receptor like the binding subunits of the insulin and IGF I receptors is of lower molecular size than the corresponding receptors in rat liver. This difference is due to differences in N-linked glycosylation

  11. The bovine placenta: a specific radioreceptor assay for both insulin-like growth factor I and insulin-like growth factor II

    International Nuclear Information System (INIS)

    Buul-Offers, S. van; Hoogerbrugge, C.M.; Poorter, T.L. de

    1988-01-01

    Binding of labelled IGF-I and IGF-II was studied to bovine, ovine and human placental cell membranes. The data show a preponderance of type I receptors in human placental membranes, and of type II receptors in ovine placental membranes, confirming reported data. In contrast, bovine placental membranes are rich in both type I and type II receptors. Therefore, the bovine placenta offers a good model for measuring specifically IGF-I (cross-reactivity with IGF-II 7 %) and IGF-II (cross-reactivity with IGF-I 4 %). By Scatchard analysis the apparent Kd (1-1.36 nmol/l) for the high affinity binding sites of the type I receptor is similar in all three preparations. Total binding capacity in ovine placental membranes is, however, 4 times lower. The affinity for the type II receptor is lower than for type I, whereas total binding capacity is higher. Affinity crosslinking confirms the competition experiments, showing binding of IGF-I to typical type I and of IGF-II to type II receptors. (author)

  12. Associations between plasma insulin-like growth factor-I and the markers of inflammation interleukin 6, C-reactive protein and YKL-40 in an elderly background population

    DEFF Research Database (Denmark)

    Andreassen, Mikkel; Raymond, Ilan; Hildebrandt, Per

    2010-01-01

    The objective of the present study was to test the hypothesis that circulating levels of insulin-like growth factor-I (IGF-I) are inversely associated with inflammatory processes in an elderly background population....

  13. Prognostic value of insulinlike growth factor I and its binding protein in patients with alcohol-induced liver disease. EMALD group

    DEFF Research Database (Denmark)

    Møller, Søren; Becker, Povl Ulrik; Juul, A

    1996-01-01

    , and immunoglobulin (Ig) M. When IGF-I or IGFBP-3 were added into this model, a Cox regression analysis showed that either had a significant independent prognostic value. Because IGF-I and IGFBP-3 were closely correlated, they contained almost the same prognostic information. Inclusion of IGF-I gave these results......Insulinlike growth factor I (IGF-I) is a single-polypeptide chain with important anabolic and endocrine activities. The liver is the major source of IGF-I and its binding protein, IGFBP-3. Circulating concentrations of IGF-I and IGFBP-3 are decreased in patients with chronic liver disease...... and correlate with the severity. The aim of this study was to assess the additional prognostic value of IGF-I and IGFBP-3 in patients entered in a large multicenter study (EMALD). Three hundred thirty-seven patients with alcohol-induced liver disease were studied in a randomized placebo-controlled trial...

  14. 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

    , 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...... treatment with GnRH in combination with an antiandrogen (cyproterone acetate) to block the possible effect of adrenal androgens has not previously been evaluated. We, therefore, studied 40 patients with idiopathic CPP that were treated for 24 months with either GnRH analog (Buserelin) in combination...... with cyproterone acetate (Androcur; n = 23) or with long acting GnRH analog (Decapeptyl Depot; n = 17). We found that serum IGF-I levels were increased before treatment in both groups (mean +/- SE, 446 +/- 35 and 391 +/- 35 micrograms/L; P

  15. Changes in calcitropic hormones, bone markers and insulin-like growth factor I (IGF-I) during pregnancy and postpartum: a controlled cohort study

    DEFF Research Database (Denmark)

    Liendgaard, Ulla Kristine Møller; við Streym, Susanna; Mosekilde, Leif

    2012-01-01

    weeks postpartum. The controls were followed in parallel. RESULTS: P-estradiol (E(2)), prolactin and 1,25-dihydroxyvitamin D (1,25(OH)(2)D) increased (p growth factor I (IGF......Pregnancy and lactation cause major changes in calcium homeostasis and bone metabolism. This population-based cohort study presents the physiological changes in biochemical indices of calcium homeostasis and bone metabolism during pregnancy and lactation INTRODUCTION: We describe physiological...... changes in calcium homeostasis, calcitropic hormones and bone metabolism during pregnancy and lactation. METHODS: We studied 153 women planning pregnancy (n = 92 conceived) and 52 non-pregnant, age-matched female controls. Samples were collected prior to pregnancy, once each trimester and 2, 16 and 36...

  16. Massive weight loss restores 24-hour growth hormone release profiles and serum insulin-like growth factor-I levels in obese subjects

    DEFF Research Database (Denmark)

    Rasmussen, M H; Hvidberg, A; Juul, A

    1995-01-01

    In the present study, we 1) determined whether the impaired spontaneous 24-h GH secretion as well as the blunted GH response to provocative testing in obese subjects are persistent disorders or transient defects reversed with weight loss and 2) investigated 24-h urinary GH excretion and basal...... levels of insulin-like growth factor-I (IGF-I), IGF-binding protein-3 (IGFBP-3), as well as insulin in obese subjects before and after a massive weight loss. We studied 18 obese subjects (age, 26 +/- 1 yr; body mass index, 40.9 +/- 1.1 kg/m2); 18 normal age-, and sex-matched control subjects; and 9...... reversible defects in 24-h spontaneous GH release profiles, basal IGF-I levels, and the IGF-I/IGFBP-3 molar ratio in obese subjects. The recovery of the 24-h GH release points to an acquired transient defect rather than a persistent preexisting disorder....

  17. 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

    between IGF-I and IGFBP-3 (i.e. free biologically active IGF-I) declined concomitantly with a decrease in growth velocity. Serum levels of IGF-I and IGFBP-3 (expressed as the SD score for bone age), but not those of estradiol, correlated with height velocity before and during treatment (r = 0.34; P ...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...

  18. Lipophorin Receptor: The Insect Lipoprotein Receptor

    Indian Academy of Sciences (India)

    IAS Admin

    physiology and develop- mental biology of silkworms, and use of silk in industrial applications. The low-density lipoprotein receptor (LDLR), one of the best characterized cell-surface receptors, mediates cholesterol ho- meostasis and other functions in mammals. The members of the LDLR superfamily are structurally related ...

  19. Lipophorin Receptor: The Insect Lipoprotein Receptor

    Indian Academy of Sciences (India)

    Permanent link: http://www.ias.ac.in/article/fulltext/reso/018/08/0748-0755. Keywords. Low-density lipoprotein receptor; lipophorin; lipophorin receptor; insects. Author Affiliations. G Ravikumar1 N B Vijayaprakash1. Seri-biotech Research Laboratory Central Silk Board Kodathi, Carmelaram Post Bangalore 560 035, India.

  20. Acetylcholine receptor antibody

    Science.gov (United States)

    ... this page: //medlineplus.gov/ency/article/003576.htm Acetylcholine receptor antibody To use the sharing features on this page, please enable JavaScript. Acetylcholine receptor antibody is a protein found in the blood ...

  1. The growth hormone dependent serine protease inhibitor, Spi 2.1 inhibits the des (1-3) insulin-like growth factor-I generating protease.

    Science.gov (United States)

    Maake, C; Yamamoto, H; Murphy, L J

    1997-12-01

    The conversion of insulin-like growth factor-I (IGF-I) to the biologically more active des (1-3) IGF-I variant is catalyzed by a ubiquitous protease. This proteolytic activity is inhibited by human alpha1-antitrypsin and soy-bean trypsin inhibitor and is up-regulated in serum and tissue extracts of hypophysectomized rats. These observations lead us to investigate whether the growth hormone regulated, serine protease inhibitor, Spi 2.1 was able to inhibit the des (1-3) IGF-I generating protease. Dihydrofolate reductase deficient Chinese hamster ovary (CHO(dhfr-ve)) cells were transfected with a rat Spi 2.1 expression vector containing the dhfr and neomycin resistance gene. Stable transfectants were selected using G418 and amplified using methotrexate. Conditioned medium from Spi 2.1 transfected CHO cells potently inhibited proteolytic activity directed against a synthetic hexa-peptide with a sequence identical to the N-terminal of IGF-I. In contrast conditioned medium from wild-type CHO cells had little effect. Based upon these observations we suggest that our previous finding of enhanced des (1-3) IGF-I generating protease activity in growth hormone deficient rats may be, at least partly explained by reduced levels of Spi 2.1. Furthermore, we propose that the regulation of the generation of des (1-3) IGF-I may be an additional potential site of growth hormone regulation of IGF-I action.

  2. Survivin as a Novel Biomarker in the Pathogenesis of Acne Vulgaris and Its Correlation to Insulin-Like Growth Factor-I.

    Science.gov (United States)

    Assaf, Hanan A; Abdel-Maged, Wafaa M; Elsadek, Bakheet E M; Hassan, Mohammed H; Adly, Mohamed A; Ali, Soher A

    2016-01-01

    Survivin, a member of the inhibitor of apoptosis protein family, has an important role in cell cycle regulation. Insulin-like growth factor-I (IGF-I) is a polypeptide hormone with wide range of biologic effects including stimulation of lipogenesis in sebaceous glands. Their overexpression in some fibrotic disorders suggests a possible implication of both IGF-I and survivin in the pathogenesis of acne and/or acne scars. The current study aimed to assess and correlate serum levels of IGF-I and survivin in patients with active acne vulgaris and postinflammatory acne scars and to evaluate their lesional expressions in comparison to healthy controls. Serum IGF-I and survivin were estimated using commercially available ELISA kits and their tissues expressions were investigated using Western blotting. Our findings suggest that IGF-I and survivin could play potential roles in the pathogenesis of active acne vulgaris and more importantly in postinflammatory acne scars with significant positive correlation coefficient between serum levels of IGF-I and survivin which support IGF-I-/PI3K-/AKT-mediated downregulation of nuclear expression of FoxO transcription factors resulting in enhanced survivin expression.

  3. Neuroprotective efficacy of subcutaneous insulin-like growth factor-I administration in normotensive and hypertensive rats with an ischemic stroke.

    Science.gov (United States)

    De Geyter, D; Stoop, W; Sarre, S; De Keyser, J; Kooijman, R

    2013-10-10

    The aim of this study was to test the insulin-like growth factor-I (IGF-I) as a neuroprotective agent in a rat model for ischemic stroke and to compare its neuroprotective effects in conscious normotensive and spontaneously hypertensive rats. The effects of subcutaneous IGF-I injection were investigated in both rat strains using the endothelin-1 rat model for ischemic stroke. Motor-sensory functions were measured using the Neurological Deficit Score. Infarct size was assessed by Cresyl Violet staining. Subcutaneous administration of IGF-I resulted in significantly reduced infarct volumes and an increase in motor-sensory functions in normotensive rats. In these rats, IGF-I did not modulate blood flow in the striatum and had no effect on the activation of astrocytes as assessed by GFAP staining. In hypertensive rats, the protective effects of IGF-I were smaller and not always significant. Furthermore, IGF-I significantly reduced microglial activation in the cortex of hypertensive rats, but not in normotensive rats. More detailed studies are required to find out whether the reduction by IGF-I of microglial activation contributes to an impairment IGF-I treatment efficacy. Indeed, we have shown before that microglia in hypertensive rats have different properties compared to those in control rats, as they exhibit a reduced responsiveness to ischemic stroke and lipopolysaccharide. Copyright © 2013 IBRO. Published by Elsevier Ltd. All rights reserved.

  4. Alleviation of body weight loss by dietary methionine is independent of insulin-like growth factor-I in protein-starved young chickens.

    Science.gov (United States)

    Nagao, Kenji; Oki, Mai; Tsukada, Akira; Kita, Kazumi

    2011-08-01

    It is well known that in protein-starved chickens, small amounts of amino acid supplement, especially methionine, reduces nitrogen excretion and thereby improves nitrogen balance. On the other hand, excess intake of methionine causes growth depression and the growth-depressive effect of excess methionine can be alleviated by consumption of dietary glycine. Insulin-like growth factor-I (IGF-I) is one of various growth-promoting factors relating to the efficiency of animal production and is known to be very sensitive to changes in nutritional status. In the present study, the interactive effect of glycine on nitrogen sparing effect of methionine in protein-starved chickens was examined. In addition, the relation of IGF-I and its specific binding protein to the nitrogen sparing effect of supplemented methionine was also investigated. Two-days refeeding of methionine supplemented to protein-free diet could promptly alleviate body weight loss in protein-starved chickens, and the alleviation of body weight loss by methionine was not improved by glycine supplements. Moreover, such acute alleviation of body weight loss by dietary methionine was independent of the change in plasma IGF-I concentration. 2011 The Authors. Animal Science Journal © 2011 Japanese Society of Animal Science.

  5. Serum insulin-like growth factor I (IGF-I) and IGF-binding protein 3 (IGFBP-3) in IVF patients with polycystic ovary syndrome: correlations with outcome.

    Science.gov (United States)

    Schoyer, Katherine D; Liu, Hung-Ching; Witkin, Steven; Rosenwaks, Zev; Spandorfer, Steven D

    2007-07-01

    To evaluate serum insulin-like growth factor I (IGF-I) and IGF-binding protein 3 (IGFBP-3) levels during stimulation in polycystic ovary syndrome (PCOS) and control populations as factors predictive of IVF outcome. Observational study. Academic medical center-based IVF practice. Forty-three PCOS and 33 male-factor control patients undergoing IVF from 2002 to 2004. Treatment with a dual suppression protocol incorporating oral contraceptive pills (OCPs) and GnRH agonist suppression followed by low-dose gonadotropin therapy. The PCOS and control patients' serum IGF-I and IGFBP-3 levels were compared and correlated with IVF outcome. PCOS and control patients were comparable in terms of demographics and IVF outcome. In both, mean serum IGF-I levels increased during stimulation. PCOS patients whose IGF-I levels decreased from day 3 to day of hCG had a significantly higher mean number of immature oocytes retrieved (4.8 +/- 1.1 vs. 2.4 +/- 0.4; P=.02). IGFBP-3 levels increased during stimulation in PCOS patients but tended to decrease in control patients. In PCOS patients, an increase in IGFBP-3 levels during stimulation was associated with a greater likelihood of becoming pregnant (P=.03) and of ongoing pregnancy (P=.02). The bioavailability of IGF-I appears to play a key role in oocyte maturation in PCOS patients. Alterations in IGFBP-3 concentration during stimulation may be a critical mechanism in modulating IGF-I activity.

  6. Short-term effects of replacing milk with cola beverages on insulin-like growth factor-I and insulin–glucose metabolism:

    DEFF Research Database (Denmark)

    Hoppe, Camilla; Kristensen, Mette; Boiesen, Marlene

    2009-01-01

    In the Western world, a trend towards increased consumption of carbonated soft drinks combined with a decreasing intake of milk is observed. This may affect circulating insulin-like growth factor I (IGF-I) and fasting insulin, as seen in pre-pubertal children. The present study was designed...... given a low-Ca diet in two 10 d periods with 10 d washout in between. In one period, they drank 2·5 litres of Coca Colaw per day and the other period 2·5 litres of semi-skimmed milk. Serum IGF-I, IGFBP-3 (RIA), insulin (fluoro immunoassay) and glucose (Cobas) were determined at baseline and end point...... of each intervention period. Insulin resistance and b-cell function were calculated with the homeostasis model assessment. A decrease in serum IGF-I was observed in the cola period compared with the milk period (P,0·05). No effects of treatment were observed on IGFBP-3, IGF-I:IGFBP-3, insulin, glucose...

  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. Acquisition of complement inhibitor serine protease factor I and its cofactors C4b-binding protein and factor H by Prevotella intermedia.

    Directory of Open Access Journals (Sweden)

    Sven Malm

    Full Text Available Infection with the Gram-negative pathogen Prevotella intermedia gives rise to periodontitis and a growing number of studies implies an association of P. intermedia with rheumatoid arthritis. The serine protease Factor I (FI is the central inhibitor of complement degrading complement components C3b and C4b in the presence of cofactors such as C4b-binding protein (C4BP and Factor H (FH. Yet, the significance of complement inhibitor acquisition in P. intermedia infection and FI binding by Gram-negative pathogens has not been addressed. Here we show that P. intermedia isolates bound purified FI as well as FI directly from heat-inactivated human serum. FI bound to bacteria retained its serine protease activity as shown in degradation experiments with (125I-labeled C4b. Since FI requires cofactors for its activity we also investigated the binding of purified cofactors C4BP and FH and found acquisition of both proteins, which retained their activity in FI mediated degradation of C3b and C4b. We propose that FI binding by P. intermedia represents a new mechanism contributing to complement evasion by a Gram-negative bacterial pathogen associated with chronic diseases.

  9. Acquisition of complement inhibitor serine protease factor I and its cofactors C4b-binding protein and factor H by Prevotella intermedia.

    Science.gov (United States)

    Malm, Sven; Jusko, Monika; Eick, Sigrun; Potempa, Jan; Riesbeck, Kristian; Blom, Anna M

    2012-01-01

    Infection with the Gram-negative pathogen Prevotella intermedia gives rise to periodontitis and a growing number of studies implies an association of P. intermedia with rheumatoid arthritis. The serine protease Factor I (FI) is the central inhibitor of complement degrading complement components C3b and C4b in the presence of cofactors such as C4b-binding protein (C4BP) and Factor H (FH). Yet, the significance of complement inhibitor acquisition in P. intermedia infection and FI binding by Gram-negative pathogens has not been addressed. Here we show that P. intermedia isolates bound purified FI as well as FI directly from heat-inactivated human serum. FI bound to bacteria retained its serine protease activity as shown in degradation experiments with (125)I-labeled C4b. Since FI requires cofactors for its activity we also investigated the binding of purified cofactors C4BP and FH and found acquisition of both proteins, which retained their activity in FI mediated degradation of C3b and C4b. We propose that FI binding by P. intermedia represents a new mechanism contributing to complement evasion by a Gram-negative bacterial pathogen associated with chronic diseases.

  10. Regulation of the pituitary tumor transforming gene by insulin-like-growth factor-I and insulin differs between malignant and non-neoplastic astrocytes

    International Nuclear Information System (INIS)

    Chamaon, Kathrin; Kirches, Elmar; Kanakis, Dimitrios; Braeuninger, Stefan; Dietzmann, Knut; Mawrin, Christian

    2005-01-01

    The reasons for overexpression of the oncogene pituitary tumor transforming gene (PTTG) in tumors are still not fully understood. A possible influence of the insulin-like growth factor I (Igf-I) may be of interest, since enhanced Igf-I signalling was reported in various human tumors. We examined the influence of Igf-I and insulin on PTTG expression in human astrocytoma cells in comparison to proliferating non-neoplastic rat embryonal astrocytes. PTTG mRNA expression and protein levels were increased in malignant astrocytes treated with Igf-I or insulin, whereas in rat embryonic astrocytes PTTG expression and protein levels increased only when cells were exposed to Igf-I. Enhanced transcription did not occur after treatment with inhibitors of phosphoinositol-3-kinase (PI3K) and mitogen-activated protein kinase (MAPK), blocking the two basic signalling pathways of Igf-I and insulin. In addition to this transcriptional regulation, both kinases directly bind to PTTG, suggesting a second regulatory route by phosphorylation. However, the interaction of endogenous PTTG with MAPK and PI3K, as well as PTTG phosphorylation were independent from Igf-I or insulin. The latter results were also found in human testis, which contains high PTTG levels as well as in nonneoplastic astrocytes. This suggest, that PI3K and MAPK signalling is involved in PTTG regulation not only in malignant astrocytomas but also in non-tumorous cells

  11. Parathyroid hormone blocks the stimulatory effect of insulin-like growth factor-I on collagen synthesis in cultured 21-day fetal rat calvariae

    International Nuclear Information System (INIS)

    Kream, B.E.; Petersen, D.N.; Raisz, L.G.

    1990-01-01

    We examined the interaction of parathyroid hormone (PTH) and recombinant human insulin-like growth factor I (IGF-I) on collagen synthesis in 21-day fetal rat calvariae as assessed by measuring the incorporation of [ 3 H]proline into collagenase-digestible protein. After 96 hours of culture, 10 nM PTH antagonized the stimulation of collagen synthesis and partially blocked the increase in dry weight produced by 10 nM IGF-I. The effect of PTH to block IGF-I stimulated collagen synthesis was observed in the central bone of calvariae and was mimicked by forskolin and phorbol 12-myristate 13-acetate, but not by 1,25-dihydroxyvitamin D3, transforming growth factor-alpha or dexamethasone. Our data are consistent with the concept that the direct effect of PTH is to inhibit basal CDP labeling and fully oppose IGF-I stimulated CDP labeling. The finding that this effect of PTH is mimicked by forskolin and PMA suggests that this block in IGF-I stimulation of CDP labeling involves both cAMP and protein kinase C mediated pathways

  12. Changes in calcitropic hormones, bone markers and insulin-like growth factor I (IGF-I) during pregnancy and postpartum: a controlled cohort study.

    Science.gov (United States)

    Møller, U K; Streym, S; Mosekilde, L; Heickendorff, L; Flyvbjerg, A; Frystyk, J; Jensen, L T; Rejnmark, L

    2013-04-01

    Pregnancy and lactation cause major changes in calcium homeostasis and bone metabolism. This population-based cohort study presents the physiological changes in biochemical indices of calcium homeostasis and bone metabolism during pregnancy and lactation We describe physiological changes in calcium homeostasis, calcitropic hormones and bone metabolism during pregnancy and lactation. We studied 153 women planning pregnancy (n=92 conceived) and 52 non-pregnant, age-matched female controls. Samples were collected prior to pregnancy, once each trimester and 2, 16 and 36 weeks postpartum. The controls were followed in parallel. P-estradiol (E2), prolactin and 1,25-dihydroxyvitamin D (1,25(OH)2D) increased (phormone (P-PTH) and calcitonin decreased (pgrowth factor I (IGF-I) was suppressed (pbone resorption and formation rose and fall, respectively (pbone formation markers increased in association with IGF-I changes (pbone turnover markers were associated with lactation status (pbone markers indicated a negative bone balance. The rise in bone formation in late pregnancy may be initiated by a spike in IGF-I levels. The high bone turnover in lactating women may be related to high prolactin and PTH levels, low E2 levels and perhaps increased parathyroid hormone-related protein levels.

  13. Androgen receptor abnormalities

    NARCIS (Netherlands)

    A.O. Brinkmann (Albert); G.G.J.M. Kuiper (George); C. Ris-Stalpers (Carolyn); H.C.J. van Rooij (Henri); G. Romalo (G.); G. Trifiro (Gianluca); E. Mulder (Eppo); L. Pinsky (L.); H.U. Schweikert (H.); J. Trapman (Jan)

    1991-01-01

    markdownabstract__Abstract__ The human androgen receptor is a member of the superfamily of steroid hormone receptors. Proper functioning of this protein is a prerequisite for normal male sexual differentiation and development. The cloning of the human androgen receptor cDNA and the elucidation of

  14. Androgen receptor abnormalities

    NARCIS (Netherlands)

    Brinkmann, A. O.; Kuiper, G. G.; Ris-Stalpers, C.; van Rooij, H. C.; Romalo, G.; Trifiro, M.; Mulder, E.; Pinsky, L.; Schweikert, H. U.; Trapman, J.

    1991-01-01

    The human androgen receptor is a member of the superfamily of steroid hormone receptors. Proper functioning of this protein is a prerequisite for normal male sexual differentiation and development. The cloning of the human androgen receptor cDNA and the elucidation of the genomic organization of the

  15. Enteral nutrients potentiate the intestinotrophic action of glucagon-like peptide-2 in association with increased insulin-like growth factor-I responses in rats

    DEFF Research Database (Denmark)

    Liu, Xiaowen; Murali, Sangita G; Holst, Jens Juul

    2008-01-01

    of GLP-2 and IGF-I system components are increased with the mucosal growth induced by enteral nutrient (EN) and/or a low dose of GLP-2 in parentally-fed rats. Rats were randomized to 4 treatment groups using a 2x2 design and maintained with parental nutrition (PN) for 7 days: PN alone, EN, GLP-2, EN......: parenteral nutrition, GLP-2 receptor, IGF binding protein-3 and -5, proglucagon....

  16. An ER activity profile including ER, PR, Bcl-2 and IGF-IR may have potential as selection criterion for letrozole or tamoxifen treatment of patients with advanced breast cancer

    DEFF Research Database (Denmark)

    Henriksen, Katrine L; Rasmussen, Birgitte B; Lykkesfeldt, Anne E

    2009-01-01

    microarrays from formalin fixed paraffin embedded primary tumor material from a subgroup of patients (9.4%), who have participated in the international, randomized, phase III clinical trial PO25 comparing letrozole with tamoxifen in 907 patients with advanced breast cancer. The expression levels of ER...

  17. Successful 6-month endurance training does not alter insulin-like growth factor-I in healthy older men and women.

    Science.gov (United States)

    Vitiello, M V; Wilkinson, C W; Merriam, G R; Moe, K E; Prinz, P N; Ralph, D D; Colasurdo, E A; Schwartz, R S

    1997-05-01

    Lean body mass, strength, and endurance decline with advancing age, changes paralleled by declines in anabolic hormones, including growth hormone (GH) and insulin-like growth factor-I (IGF-I). Acute exercise has been shown to stimulate the GH/IGF-I axis, and long-term exercise increases GH. This study examined the effect of endurance training on IGF-I in healthy older men and women. Thirty-one healthy older men (66.9 +/- 1.0 yrs, mean +/- SEM) and 21 healthy older women (67.1 +/- 1.7 yrs) were randomized to either 3d/wk, 6-month endurance (ET3) or stretching/flexibility (SF3) protocols. Another group of 15 healthy older men (69.0 +/- 1.3 yrs) participated in a more intensive 5d/wk, 6-month endurance protocol (ET5). Before and after training, subjects were weight stabilized and participated in maximal exercise tolerance testing, body composition assessment, and fasting blood sampling. ET3 training resulted in a significant increase (14%) in maximal aerobic power (VO2max), significant decreases in body weight (BW), fat mass (FM), and waist/hip ratio (WHR), and a significant increase in fat-free mass (FFM). No significant VO2max or body composition changes were observed in the SF3 group. For the ET5 group, a significant increase (22%) in VO2max and significant decrease in BW, FM, and WHR were observed. No significant changes in IGF-I were observed for any of the three groups. Pre- versus post-training IGF-I values were very stable (r = .86, p decrease measures of body adiposity did not significantly increase basal levels of IGF-I in healthy older men and women.

  18. Seasonal regulation of the growth hormone-insulin-like growth factor-I axis in the American black bear (Ursus americanus).

    Science.gov (United States)

    Blumenthal, Stanley; Morgan-Boyd, Rebecca; Nelson, Ralph; Garshelis, David L; Turyk, Mary E; Unterman, Terry

    2011-10-01

    The American black bear maintains lean body mass for months without food during winter denning. We asked whether changes in the growth hormone/insulin-like growth factor-I (GH-IGF-I) axis may contribute to this remarkable adaptation to starvation. Serum IGF-I levels were measured by radioimmunoassay, and IGF-binding proteins (IGFBPs) were analyzed by ligand blotting. Initial studies in bears living in the wild showed that IGF-I levels are highest in summer and lowest in early winter denning. Detailed studies in captive bears showed that IGF-I levels decline in autumn when bears are hyperphagic, continue to decline in early denning, and later rise above predenning levels despite continued starvation in the den. IGFBP-2 increased and IGFBP-3 decreased in early denning, and these changes were also reversed in later denning. Treatment with GH (0.1 mg·kg(-1)·day(-1) × 6 days) during early denning increased serum levels of IGF-I and IGFBP-3 and lowered levels of IGFBP-2, indicating that denning bears remain responsive to GH. GH treatment lowered blood urea nitrogen levels, reflecting effects on protein metabolism. GH also accelerated weight loss and markedly increased serum levels of free fatty acids and β-hydroxybutyrate, resulting in a ketoacidosis (bicarbonate decreased to 15 meq/l), which was reversed when GH was withdrawn. These results demonstrate seasonal regulation of GH/IGF-I axis activity in black bears. Diminished GH activity may promote fat storage in autumn in preparation for denning and prevent excessive mobilization and premature exhaustion of fat stores in early denning, whereas restoration of GH/IGF activity in later denning may prepare the bear for normal activity outside the den.

  19. Glucose lowering effect of transgenic human insulin-like growth factor-I from rice: in vitro and in vivo studies

    Directory of Open Access Journals (Sweden)

    Sun Samuel SM

    2011-04-01

    Full Text Available Abstract Background Human insulin-like growth factor-I (hIGF-I is a growth factor which is highly resemble to insulin. It is essential for cell proliferation and has been proposed for treatment of various endocrine-associated diseases including growth hormone insensitivity syndrome and diabetes mellitus. In the present study, an efficient plant expression system was developed to produce biologically active recombinant hIGF-I (rhIGF-I in transgenic rice grains. Results The plant-codon-optimized hIGF-I was introduced into rice via Agrobacterium-mediated transformation. To enhance the stability and yield of rhIGF-I, the endoplasmic reticulum-retention signal and glutelin signal peptide were used to deliver rhIGF-I to endoplasmic reticulum for stable accumulation. We found that only glutelin signal peptide could lead to successful expression of hIGF-I and one gram of hIGF-I rice grain possessed the maximum activity level equivalent to 3.2 micro molar of commercial rhIGF-I. In vitro functional analysis showed that the rice-derived rhIGF-I was effective in inducing membrane ruffling and glucose uptake on rat skeletal muscle cells. Oral meal test with rice-containing rhIGF-I acutely reduced blood glucose levels in streptozotocin-induced and Zucker diabetic rats, whereas it had no effect in normal rats. Conclusion Our findings provided an alternative expression system to produce large quantities of biologically active rhIGF-I. The provision of large quantity of recombinant proteins will promote further research on the therapeutic potential of rhIGF-I.

  20. Novel Single Nucleotide Polymorphisms of the Insulin-Like Growth Factor-I Gene and Their Associations with Growth Traits in Common Carp (Cyprinus carpio L.

    Directory of Open Access Journals (Sweden)

    Xiu Feng

    2014-12-01

    Full Text Available Insulin-like growth factor-I (IGF-I plays an important role in the growth and development of vertebrates. To study polymorphisms of IGF-I, we screened a total of 4555 bp of genomic sequences in four exons and partial introns for the discovery of single nucleotide polymorphism (SNP in common carp (Cyprinus carpio. Three SNPs (g.3759T>G, g.7627T>A and g.7722T>C in intron 2 and a nonsynonymous SNP (g.7892C>T in exon 3 were identified in a pilot population including random parents and their progenies. 289 progenies were further genotyped for studying possible associations between genotypes or combined genotypes and growth traits. The results showed that the locus g.7627T>A was significantly associated with body weight and body length, and fish with genotype AA had a mean body weight 5.9% higher than those with genotype TT. No significant associations were observed between genotypes of other loci and growth traits. However, when both g.7627T>A and g.7722T>C were considered, the combined genotype TT/TT was extremely associated with the lowest values of body length and body weight and the highest K value in comparison with other diplotypes (p < 0.01. These results suggest that genotype AA at g.7627T>A and its combined genotypes with alleles from another locus have positive effects on growth traits, which would be a candidate molecular marker for further studies in marker-assisted selection in common carp.

  1. Effects of insulin-like growth factor-I and platelet-rich plasma on sciatic nerve crush injury in a rat model.

    Science.gov (United States)

    Emel, Erhan; Ergün, Selma Sönmez; Kotan, Dilcan; Gürsoy, Esra Başar; Parman, Yeşim; Zengin, Asli; Nurten, Asiye

    2011-02-01

    Local administration of insulin-like growth factor-I (IGF-I) has been shown to increase the rate of axon regeneration in crush-injured and freeze-injured rat sciatic nerves. Local administration of platelet-rich plasma (PRP) has been also shown to have a measurable effect on facial nerve regeneration after transection in a rat model. The objective of the study was to compare the effects of locally administered IGF-I and PRP on the parameters of the Sciatic Function Index (SFI), sensory function (SF), axon count, and myelin thickness/axon diameter ratio (G-ratio) in a rat model of crush-injured sciatic nerves. The right sciatic nerve of Wistar albino rats (24 animals) was crushed using a Yasargil-Phynox aneurysm clip for 45 minutes. All animals were randomly divided into 3 groups: Group 1 (control group) was treated with saline, Group 2 was treated with IGF-I, and Group 3 was treated with PRP. Injections were performed using the tissue expander's injection port with a connecting tube directed at the crush-injured site. Functional recovery was assessed with improvement in the SFI. Recovery of sensory function was using the pinch test. Histopathological examination was performed 3 months after the injury. The SFI showed an improved functional recovery in the IGF-I-treated animals (Group 2) compared with the saline-treated animals (Group 1) 30 days after the injury. In IGF-I-treated rats, sensory function returned to the baseline level significantly faster than in saline-treated and PRP-treated rats as shown in values between SF-2 and SF-7. The G-ratios were found to be significantly higher in both experimental groups than in the control group. This study suggests that the application of IGF-I to the crush-injured site may expedite the functional recovery of paralyzed muscle by increasing the rate of axon regeneration.

  2. Expression analysis of the insulin-like growth factors I and II during embryonic and early larval development of turbot ( Scophthalmus maximus)

    Science.gov (United States)

    Wen, Haishen; Qi, Qian; Hu, Jian; Si, Yufeng; He, Feng; Li, Jifang

    2015-04-01

    The insulin-like growth factors I and II (IGF-I and IGF-II) are important proteins involved in fish growth and development. Here, we report the isolation of IGF-II and expression analysis of IGFs in turbot Scophthalmus maximus, aiming to clarify their function in embryonic and larval development of fish. The deduced IGF-II gene is 808 bp in full length, which encodes a protein of 219 amino acids and is 93% similar with that of Paralichthys olicaceus in amino acid sequence. The tissue abundance and the expression pattern of IGFs in a turbot at early development stages were investigated via reverse transcription-polymer chain reaction. Result showed that the IGF-I and IGF-II genes were widely expressed in tissues of S. maximus. IGF-I was detected in all tissues except intestines with the highest level in liver, while IGF-II transcript presented in all tissues except muscle. At the stages of embryonic and larval development, the mRNA levels of IGFs sharply increased from the stage of unfertilized egg to post larva, followed by a decrease with larval development. However, there was an increase in IGF-I at the embryonic stage and IGF-II at the gastrula stage, respectively. These results suggested that IGFs play important roles in cell growth and division of the turbot. Our study provides reference data for further investigation of growth regulation in turbot, which can guarantee better understanding of the physiological role that IGFs play in fish.

  3. Yersinia pestis Ail recruitment of C4b-binding protein leads to factor I-mediated inactivation of covalently and noncovalently bound C4b.

    Science.gov (United States)

    Ho, Derek K; Skurnik, Mikael; Blom, Anna M; Meri, Seppo

    2014-03-01

    The outer membrane protein Ail of Yersinia pestis mediates several virulence functions, including serum resistance. Here, we demonstrate that Ail binds C4b-binding protein (C4BP), the primary fluid-phase regulator of the classical and lectin pathways. Non-covalent binding of C4 and C4b to Ail was also observed. C4BP bound to Ail can act as a cofactor to the serine protease factor I (fI) in the cleavage of fluid-phase C4b. Employing a panel of C4BP alpha-chain mutants, we observed that the absence of complement control protein domain 6 and 8 reduced binding to Ail. Immunoblot analysis of normal human serum (NHS)-treated bacteria revealed minimal C4b alpha'-chain complexes with bacterial outer membrane targets. Addition of the anti-C4BP monoclonal antibody MK104 to NHS restored C4b-alpha' chain target complexes, suggesting that C4b binds covalently to targets on the Y. pestis surface. C4b bound to Ail noncovalently was also cleaved in a C4BP and fI-dependent manner, leaving the C4c fragment bound to Ail. MK104 also prevented the cleavage of noncovalently bound C4b. Collectively, these data suggest that when C4BP is bound to Ail, fI can cleave and inactivate C4b that has bound covalently to bacterial surface structures as well as C4b bound noncovalently to Ail. © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  4. Levels of insulin, insulin-like growth factor-I and thyroid hormones in relation to the body condition score changes in periparturient dairy cows

    Directory of Open Access Journals (Sweden)

    Fratrić Natalija

    2013-01-01

    Full Text Available The objective of this study was to determine the levels of insulin, insulin like growth factor I (IGF-I and thyroid hormones in relation to the body condition score (BCS of periparturient dairy cows. The study was carried out on twenty Holstein-Friesian dairy cows with average milk production of 7000 L/305 days in the previous lactation, parity ranging from 2-4. All cows were BCS scored during the early dry period, 7±3 days before and after parturition. Based on the BCS at the early dry period, cows were divided in two groups: cows with high BCS (3.75- 4.25, HBCS, n=10, and cows with moderate BCS (2.75-3.75, MBCS, n=10. Blood samples were taken at the time of BCS evaluation. Concentrations of insulin, IGF-I, triiodothyroinine (T3 and thyroxine (T4 were determined by radioimmunoassay (RIA, INEP-Zemun, Serbia. Statistical differences between mean values were determined using Student t-test (p0.05. IGF-I level in HBCS cows at days 7±3 before calving was significantly higher (16.28±3.07:11.76±2.28, p<0.01, with a reverse relationship after calving (3.77±1.64:8.46±2.37, p<0.01. Insulin level was significantly lower at 7±3 days before calving in HBCS cows (16.26±4.60:20.18±4.96mIU/L, p<0.05. Thyroid hormones levels were significantly lower in HBCS group et all examined periods. [Projekat Ministarstva nauke Republike Srbije, br. III 46002 i br. 31003

  5. Impact of nutrients on insulin-like growth factor-I, insulin-like growth factor binding protein-3 and their ratio in African American and white males.

    Science.gov (United States)

    McGreevy, Katharine M; Hoel, Brian D; Lipsitz, Stuart R; Hoel, David G

    2007-01-01

    Higher levels of insulin-like growth factor-I (IGF-I) and lower levels of IGF binding protein-3 (IGFBP-3) have been associated with an increased risk of prostate cancer. Nutrition is known to partially regulate IGF levels and it is possible that nutritional factors mediate the impact of IGF levels on prostate cancer risk. A cross-sectional analysis of the impact of nutritional factors measured by a dietary questionnaire on plasma levels of IGF-I, IGFBP-3 and their molar ratio. Multiple linear regression analysis was used to test for effects of nutrients on IGF levels. Prostate cancer screening at the Hollings Cancer Center in Charleston, South Carolina. Ninety-five African American and 138 white males aged 33-83 years attending the screening. In whites, intakes of total, saturated and monounsaturated fats were positively associated with an increase in the molar ratio, while there was no association in African Americans. In African Americans, we found that increasing intake of calcium and dairy servings was positively associated with IGF-I levels. Increased vegetable intake was positively associated with IGFBP-3 in African Americans, while there was no effect in whites. A higher percentage of alcohol in the total diet was significantly associated with a decrease in the molar ratio and an increase in IGFBP-3 in both groups. Our results confirm previous findings of nutritional determinants of IGF levels. Additionally, we found the impact of several nutrients on IGF levels to be different in whites and African Americans, which warrants further investigation.

  6. Involvement of G proteins in the effect of insulin-like growth factor I on gonadotropin-induced rat granulosa cell differentiation.

    Science.gov (United States)

    He, H; Herington, A C; Roupas, P

    1994-03-01

    Insulin-like growth factor I (IGF-I) promotes gonadotropin-induced granulosa cell differentiation and proliferation. In order to investigate whether guanine nucleotide binding proteins (G proteins) may be linked, directly or indirectly, to some of the actions of IGF, the effects of cholera toxin (CT) and pertussis toxin (PT) on the enhancement by IGF-I of PMSG (pregnant mare serum gonadotropin)-induced rat granulosa cell differentiation have been studied. This was done by the determination of progesterone production, aromatase activity and cAMP accumulation after a 48 h incubation with PMSG, IGF-I and PMSG plus IGF-I in cells treated with either CT or PT. Both CT and PT treatment stimulated PMSG-induced progesterone production in granulosa cells after 48 h of culture with PMSG. CT treatment also stimulated aromatase activity in cells treated with PMSG and increased cAMP secretion under basal conditions (untreated cells) and in PMSG treated cells. Both CT and PT increased the stimulation by IGF-I of PMSG-induced progesterone production after 48 h of culture with PMSG plus IGF-I. Furthermore, CT augmented the enhancement by IGF-I of PMSG-induced aromatase activity and cAMP accumulation. In the absence of PMSG, CT did not increase steroidogenesis either alone or in the presence of IGF-I within the time frame studied even though CT was able to stimulate cAMP accumulation in untreated and IGF-I treated cells. These results suggest that G proteins have a role in the signalling cascade involved in gonadotropin-induced granulosa cell differentiation measured as PMSG-mediated steroidogenesis.(ABSTRACT TRUNCATED AT 250 WORDS)

  7. Chronic alcohol consumption, type 2 diabetes mellitus, insulin-like growth factor-I (IGF-I), and growth hormone (GH) in ethanol-treated diabetic rats.

    Science.gov (United States)

    Kim, Soo-Jeong; Ju, Anes; Lim, Seul-Gi; Kim, Dai-Jin

    2013-11-13

    Alcohol has deleterious influences on glucose metabolism which may contribute to the development of type 2 diabetes mellitus (T2DM). Insulin-like growth factor I (IGF-I) and growth hormone (GH), which interact with insulin to modulate metabolic control, have been shown to be related to impaired glucose tolerance. This study was conducted to assess the possibility that altered circulating IGF-I and GH levels contribute to the exacerbation of T2DM by alcohol use in type 2 diabetic Otsuka Long-Evans Tokushima Fatty (OLETF) rats and non-diabetic Long-Evans Tokushima Otsuka (LETO) rats. OLETF rats were pair-fed a Lieber-DeCarli Regular Ethanol diet and LETO rats were pair-fed a control diet for 6 weeks. At 6 weeks, an Intraperitoneal Glucose Tolerance Test (IP-GTT) was performed and IGF-I and GH levels were evaluated. Prior to an IP-GTT, OLETF-Ethanol (O-E) group had significantly a decrease in the mean glucose levels compared to OLETF-Control (O-C) group. At 120 min post IP-GTT, the O-E group had significantly an increase in the mean glucose levels compared to O-C group. The serum IGF-I levels were significantly lower and the serum GH levels were significantly higher in the O-E group than in L-C group. These results suggest that IGF-I and GH are prominent in defining the risk and development of T2DM, and may be adversely affected by heavy alcohol use, possibly mediating its diabetogenic effects. Thus, the overall glucose intolerance in the setting of alcoholism may be attributable to inappropriate alteration of IGF-I and GH levels. © 2013. Published by Elsevier Inc. All rights reserved.

  8. Synergistic effect of fadrozole and insulin-like growth factor-I on female-to-male sex reversal and body weight of broiler chicks.

    Science.gov (United States)

    Mohammadrezaei, Mohammad; Toghyani, Majid; Gheisari, Abbasali; Toghyani, Mehdi; Eghbalsaied, Shahin

    2014-01-01

    The aim of this study was to investigate the effects of Fadrozole hydrochloride and recombinant human insulin-like growth factor I (rhIGF-I) on female-to-male sex reversal, hatching traits, and body weight of broiler chickens. On the third day of incubation, fertile eggs were randomly assigned to five experimental groups comprising (i) Fadrozole (0.1 mg/egg), (ii) rhIGF-I (100 ng/egg), (iii) Fadrozole (0.1 mg/egg) + rhIGF-I (100 ng/egg), (iv) vehicle injection (10 mM acetic acid and 0.1% BSA), and (v) non-injected eggs. Eggs in the rhIGF-I-injected groups showed the mode of hatching time at the 480th hour of incubation, 12 hours earlier compared to the other groups, with no statistically significant difference in mortality and hatchability. On Day 1 and 42 of production, 90% of genetically female chicks were masculinized using Fadrozole treatment, while 100% female-to-male phenotypic sex reversal was observed in the Fadrozole+rhIGF-I group. Fadrozole equalized the body weight of both genders, although rhIGF-I was effective on the body weight of male chicks only. Interestingly, combined rhIGF-I and Fadrozole could increase the body weight in both sexes compared to the individual injections (Pbody weight of masculinized chickens via Fadrozole could be equal to their genetically male counterparts, and (iv) the IGF-I effectiveness, specifically along with the application of aromatase inhibitors in female chicks, indicates that estrogen synthesis could be a stumbling block for the IGF-I action mechanism in female embryos.

  9. Insulin-like growth factor-I feedback regulation of growth hormone and luteinizing hormone secretion in the pig: evidence for a pituitary site of action.

    Science.gov (United States)

    Barb, C R; Hausman, G J

    2009-06-01

    Three experiments (EXP) were conducted to determine the role of insulin-like growth factor-I (IGF-I) in the control of growth hormone (GH) and LH secretion. In EXP I, prepuberal gilts, 65 ± 6 kg body weight and 140 days of age received intracerebroventricular (ICV) injections of saline (n = 4), 25 μg (n = 4) or 75 μg (n = 4) IGF-I and jugular blood samples were collected. In EXP II, anterior pituitary cells in culture collected from 150-day-old prepuberal gilts (n = 6) were challenged with 0.1, 10 or 1000 nM [Ala15]-h growth hormone-releasing hormone-(1-29)NH2 (GHRH), or 0.01, 0.1, 1, 10, 30 nM IGF-I individually or in combinations with 1000 nM GHRH. Secreted GH was measured at 4 and 24 h after treatment. In EXP III, anterior pituitary cells in culture collected from 150-day-old barrows (n = 5) were challenged with 10, 100 or 1000 nM gonadotropin-releasing hormone (GnRH) or 0.01, 0.1, 1, 10, 30 nM IGF-I individually or in combinations with 100 nM GnRH. Secreted LH was measured at 4 h after treatment. In EXP I, serum GH and LH concentrations were unaffected by ICV IGF-I treatment. In EXP II, relative to control all doses of GHRH increased (P 0.1). In conclusion, under these experimental conditions the results suggest that the pituitary is the putative site for IGF-I modulation of GH and LH secretion. Further examination of the role of IGF-I on GH and LH secretion is needed to understand the inhibitory and stimulatory action of IGF-I on GH and LH secretion.

  10. GABA receptor imaging

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Jong Doo [Yonsei University College of Medicine, Seoul (Korea, Republic of)

    2007-04-15

    GABA is primary an inhibitory neurotransmitter that is localized in inhibitory interneurons. GABA is released from presynaptic terminals and functions by binding to GABA receptors. There are two types of GABA receptors, GABA{sub A}-receptor that allows chloride to pass through a ligand gated ion channel and GABA{sub B}-receptor that uses G-proteins for signaling. The GABA{sub A}-receptor has a GABA binding site as well as a benzodiazepine binding sites, which modulate GABA{sub A}-receptor function. Benzodiazepine GABAA receptor imaging can be accomplished by radiolabeling derivates that activates benzodiazepine binding sites. There has been much research on flumazenil (FMZ) labeled with {sup 11}C-FMZ, a benzodiazepine derivate that is a selective, reversible antagonist to GABAA receptors. Recently, {sup 18}F-fluoroflumazenil (FFMZ) has been developed to overcome {sup 11}C's short half-life. {sup 18}F-FFMZ shows high selective affinity and good pharmacodynamics, and is a promising PET agent with better central benzodiazepine receptor imaging capabilities. In an epileptic focus, because the GABA/benzodiazepine receptor amount is decreased, using '1{sup 1}C-FMZ PET instead of {sup 18}F-FDG, PET, restrict the foci better and may also help find lesions better than high resolution MR. GABA{sub A} receptors are widely distributed in the cerebral cortex, and can be used as an viable neuronal marker. Therefore it can be used as a neuronal cell viability marker in cerebral ischemia. Also, GABA-receptors decrease in areas where neuronal plasticity develops, therefore, GABA imaging can be used to evaluate plasticity. Besides these usages, GABA receptors are related with psychological diseases, especially depression and schizophrenia as well as cerebral palsy, a motor-related disorder, so further in-depth studies are needed for these areas.

  11. GABA receptor imaging

    International Nuclear Information System (INIS)

    Lee, Jong Doo

    2007-01-01

    GABA is primary an inhibitory neurotransmitter that is localized in inhibitory interneurons. GABA is released from presynaptic terminals and functions by binding to GABA receptors. There are two types of GABA receptors, GABA A -receptor that allows chloride to pass through a ligand gated ion channel and GABA B -receptor that uses G-proteins for signaling. The GABA A -receptor has a GABA binding site as well as a benzodiazepine binding sites, which modulate GABA A -receptor function. Benzodiazepine GABAA receptor imaging can be accomplished by radiolabeling derivates that activates benzodiazepine binding sites. There has been much research on flumazenil (FMZ) labeled with 11 C-FMZ, a benzodiazepine derivate that is a selective, reversible antagonist to GABAA receptors. Recently, 18 F-fluoroflumazenil (FFMZ) has been developed to overcome 11 C's short half-life. 18 F-FFMZ shows high selective affinity and good pharmacodynamics, and is a promising PET agent with better central benzodiazepine receptor imaging capabilities. In an epileptic focus, because the GABA/benzodiazepine receptor amount is decreased, using '1 1 C-FMZ PET instead of 18 F-FDG, PET, restrict the foci better and may also help find lesions better than high resolution MR. GABA A receptors are widely distributed in the cerebral cortex, and can be used as an viable neuronal marker. Therefore it can be used as a neuronal cell viability marker in cerebral ischemia. Also, GABA-receptors decrease in areas where neuronal plasticity develops, therefore, GABA imaging can be used to evaluate plasticity. Besides these usages, GABA receptors are related with psychological diseases, especially depression and schizophrenia as well as cerebral palsy, a motor-related disorder, so further in-depth studies are needed for these areas

  12. Dengue virus receptor

    OpenAIRE

    Hidari, Kazuya I.P.J.; Suzuki, Takashi

    2011-01-01

    Dengue virus is an arthropod-borne virus transmitted by Aedes mosquitoes. Dengue virus causes fever and hemorrhagic disorders in humans and non-human primates. Direct interaction of the virus introduced by a mosquito bite with host receptor molecule(s) is crucial for virus propagation and the pathological progression of dengue diseases. Therefore, elucidation of the molecular mechanisms underlying the interaction between dengue virus and its receptor(s) in both humans and mosquitoes is essent...

  13. Therapeutic androgen receptor ligands

    Science.gov (United States)

    Allan, George F.; Sui, Zhihua

    2003-01-01

    In the past several years, the concept of tissue-selective nuclear receptor ligands has emerged. This concept has come to fruition with estrogens, with the successful marketing of drugs such as raloxifene. The discovery of raloxifene and other selective estrogen receptor modulators (SERMs) has raised the possibility of generating selective compounds for other pathways, including androgens (that is, selective androgen receptor modulators, or SARMs). PMID:16604181

  14. Prospective study of insulin-like growth factor-I, insulin-like growth factor-binding protein 3, genetic variants in the IGF1 and IGFBP3 genes and risk of coronary artery disease

    NARCIS (Netherlands)

    Ricketts, Sally L.; Rensing, Katrijn L.; Holly, Jeff M.; Chen, Li; Young, Elizabeth H.; Luben, Robert; Ashford, Sofie; Song, Kijoung; Yuan, Xin; Dehghan, Abbas; Wright, Benjamin J.; Waterworth, Dawn M.; Mooser, Vincent; Waeber, Gérard; Vollenweider, Peter; Epstein, Stephen E.; Burnett, Mary S.; Devaney, Joseph M.; Hakonarson, Hakon H.; Rader, Daniel J.; Reilly, Muredach P.; Danesh, John; Thompson, Simon G.; Dunning, Alison M.; van Duijn, Cornelia M.; Samani, Nilesh J.; McPherson, Ruth; Wareham, Nicholas J.; Khaw, Kay-Tee; Boekholdt, S. Matthijs; Sandhu, Manjinder S.

    2011-01-01

    Although experimental studies have suggested that insulin-like growth factor I (IGF-I) and its binding protein IGFBP-3 might have a role in the aetiology of coronary artery disease (CAD), the relevance of circulating IGFs and their binding proteins in the development of CAD in human populations is

  15. 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...

  16. 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

  17. Prediction of the outcome of growth hormone provocative testing in short children by measurement of serum levels of insulin-like growth factor I and insulin-like growth factor binding protein 3

    DEFF Research Database (Denmark)

    Juul, A; Skakkebaek, N E

    1997-01-01

    Serum levels of insulin-like growth factor I (IGF-I) and insulin-like growth factor binding protein 3 (IGFBP-3) reflect the secretion of endogenous growth hormone (GH) in healthy children and exhibit little diurnal variation, which makes them potential candidates for screening of GH deficiency (G...

  18. Relationship of serum insulin-like growth factor I (IGF-I) with nutritional status in pediatric patients with malignant diseases--a single Romanian center experience.

    Science.gov (United States)

    Chinceşan, Mihaela Ioana; Mărginean, Oana; Pitea, Ana-Maria; Dobreanu, Minodora

    2013-10-01

    The aim of this study was to analyze insulin-like growth factor I (IGF-I) serum level in pediatric patients with cancer compared with pediatric patients with nononcological diseases and to assess the relationship between IGF-I and nutritional status of oncological patients. From January 2009 to July 2012, we assessed 151 consecutively hospitalized patients in a tertiary emergency pediatric hospital. The patients were divided into two groups: group I, consisting of patients with malignant diseases (64 patients), and group II, the control group, consisting of 87 age- and gender-matched patients with different pediatric diseases. The anthropometric parameters (weight, height, body mass index, middle upper arm circumference (MUAC), and tricipital skinfold thickness (TST) and biochemical parameters (proteins, albumin, and total IGF-I) were comparatively evaluated at the diagnosis and after intensive chemotherapy in the malignant group. Anthropometric and biochemical parameters in group I were significantly different from those in group II for height, MUAC, TST, total proteins, and albumin (p patients with malignant diseases and 5 out of 87 patients in the control group had malnutrition. IGF-I in patients with cancer was much lower than in the control group (median 48.3 ng/ml, range 25.00-662.00 ng/ml vs 129.00 ng/ml, range 25.00-745.00 ng/ml) (p = 0.014). We found a positive correlation between IGF-I, MUAC, and TST at the diagnosis of the malignant disease. Also, we identified positive correlations between IGF-I, protein, and albumin. Serum IGF-I levels in cancer patients were significantly lower at diagnosis than after chemotherapy (48.3 ng/ml, range 25.00-662.00 ng/ml vs 110.0 ng/ml, range 25.00-573.00 ng/ml; p = 0.04). IGF-I seems to be an accurate biochemical parameter used in malnutrition assessment of children with cancer. IGF-I correlated with the anthropometric parameters of the arm, serum protein, and albumin. These parameters most accurately characterize the

  19. CCAAT/enhancer-binding protein delta activates insulin-like growth factor-I gene transcription in osteoblasts. Identification of a novel cyclic AMP signaling pathway in bone

    Science.gov (United States)

    Umayahara, Y.; Ji, C.; Centrella, M.; Rotwein, P.; McCarthy, T. L.

    1997-01-01

    Insulin-like growth factor-I (IGF-I) plays a key role in skeletal growth by stimulating bone cell replication and differentiation. We previously showed that prostaglandin E2 (PGE2) and other cAMP-activating agents enhanced IGF-I gene transcription in cultured primary rat osteoblasts through promoter 1, the major IGF-I promoter, and identified a short segment of the promoter, termed HS3D, that was essential for hormonal regulation of IGF-I gene expression. We now demonstrate that CCAAT/enhancer-binding protein (C/EBP) delta is a major component of a PGE2-stimulated DNA-protein complex involving HS3D and find that C/EBPdelta transactivates IGF-I promoter 1 through this site. Competition gel shift studies first indicated that a core C/EBP half-site (GCAAT) was required for binding of a labeled HS3D oligomer to osteoblast nuclear proteins. Southwestern blotting and UV-cross-linking studies showed that the HS3D probe recognized a approximately 35-kDa nuclear protein, and antibody supershift assays indicated that C/EBPdelta comprised most of the PGE2-activated gel-shifted complex. C/EBPdelta was detected by Western immunoblotting in osteoblast nuclear extracts after treatment of cells with PGE2. An HS3D oligonucleotide competed effectively with a high affinity C/EBP site from the rat albumin gene for binding to osteoblast nuclear proteins. Co-transfection of osteoblast cell cultures with a C/EBPdelta expression plasmid enhanced basal and PGE2-activated IGF-I promoter 1-luciferase activity but did not stimulate a reporter gene lacking an HS3D site. By contrast, an expression plasmid for the related protein, C/EBPbeta, did not alter basal IGF-I gene activity but did increase the response to PGE2. In osteoblasts and in COS-7 cells, C/EBPdelta, but not C/EBPbeta, transactivated a reporter gene containing four tandem copies of HS3D fused to a minimal promoter; neither transcription factor stimulated a gene with four copies of an HS3D mutant that was unable to bind osteoblast

  20. Somatomedin-C/insulin-like growth factor-I and Insulin-like growth factor-II mRNAs in rate fetal and adult tissues

    International Nuclear Information System (INIS)

    Lund, P.K.; Moats-Staats, B.M.; Hynes, M.A.; Simmons, J.G.; Jansen, M.; D'ercole, A.J.; Van Wyk, J.J.

    1986-01-01

    Somatomedin-C or insulin-like growth factor I (Sm-C/IGF-I) and insulin-like growth factor II (IGF-II) have been implicated in the regulation of fetal growth and development. In the present study 32 P-labeled complementary DNA probes encoding human and mouse Sm-C/IGF-I and human IGF-II were used in Northern blot hybridizations to analyze rat Sm-C/IGF-I and IGF-II mRNAs in poly(A + ) RNAs from intestine, liver, lung, and brain of adult rats and fetal rats between day 14 and 17 of gestation. In fetal rats, all four tissues contained a major mRNA of 1.7 kilobase (kb) that hybridized with the human Sm-C/IGF-I cDNA and mRNAs of 7.5, 4.7, 1.7, and 1.2 kb that hybridized with the mouse Sm-C/IGF-I cDNA. Adult rat intestine, liver, and lung also contained these mRNAs but Sm-C/IGF-I mRNAs were not detected in adult rat brain. These findings provide direct support for prior observations that multiple tissues in the fetus synthesize immunoreactive Sm-C/IGF-I and imply a role for Sm-C/IGF-I in fetal development as well as postnatally. Multiple IGF-II mRNAs of estimated sizes 4.7, 3.9, 2.2, 1.75, and 1.2 kb were observed in fetal rat intestine, liver, lung, and brain. The 4.7- and 3.9-kb mRNAs were the major hybridizing IGF-II mRNAs in all fetal tissues. Higher abundance of IGF-II mRNAs in rat fetal tissues compared with adult tissues supports prior hypotheses, based on serum IGF-II concentrations, that IGF-II is predominantly a fetal somatomedin. IGF-II mRNAs are present, however, in some poly(A + ) RNAs from adult rat tissues. The brain was the only tissue in the adult rat where the 4.7- and 3.9-kb IGF-II mRNAs were consistently detected. These findings suggest that a role for IGF-II in the adult rat, particularly in the central nervous system, cannot be excluded

  1. Insulin-like growth factors I and II in starry flounder (Platichthys stellatus): molecular cloning and differential expression during embryonic development.

    Science.gov (United States)

    Xu, Yongjiang; Zang, Kun; Liu, Xuezhou; Shi, Bao; Li, Cunyu; Shi, Xueying

    2015-02-01

    In order to elucidate the possible roles of insulin-like growth factors I and II (IGF-I and IGF-II) in the embryonic development of Platichthys stellatus, their cDNAs were isolated and their spatial expression pattern in adult organs and temporal expression pattern throughout embryonic development were examined by quantitative real-time PCR assay. The IGF-I cDNA sequence was 1,268 bp in length and contained an open reading frame (ORF) of 558 bp, which encoded 185 amino acid residues. With respect to IGF-II, the full-length cDNA was 899 bp in length and contained a 648-bp ORF, which encoded 215 amino acid residues. The amino acid sequences of IGF-I and IGF-II exhibited high identities with their fish counterparts. The highest IGF-I mRNA level was found in the liver for both sexes, whereas the IGF-II gene was most abundantly expressed in female liver and male liver, gill, and brain. The sex-specific and spatial expression patterns of IGF-I and IGF-II mRNAs are thought to be related to the sexually dimorphic growth and development of starry flounder. Both IGF-I and IGF-II mRNAs were detected in unfertilized eggs, which indicated that IGF-I and IGF-II were parentally transmitted. Nineteen embryonic development stages were tested. IGF-I mRNA level remained high from unfertilized eggs to low blastula followed by a significant decrease at early gastrula and then maintained a lower level. In contrast, IGF-II mRNA level was low from unfertilized eggs to high blastula and peaked at low blastula followed by a gradual decrease. Moreover, higher levels of IGF-I mRNA than that of IGF-II were found from unfertilized eggs to high blastula, vice versa from low blastula to newly hatched larva, and the different expression pattern verified the differential roles of IGF-I and IGF-II in starry flounder embryonic development. These results could help in understanding the endocrine mechanism involved in the early development and growth of starry flounder.

  2. Synergistic effect of fadrozole and insulin-like growth factor-I on female-to-male sex reversal and body weight of broiler chicks.

    Directory of Open Access Journals (Sweden)

    Mohammad Mohammadrezaei

    Full Text Available The aim of this study was to investigate the effects of Fadrozole hydrochloride and recombinant human insulin-like growth factor I (rhIGF-I on female-to-male sex reversal, hatching traits, and body weight of broiler chickens. On the third day of incubation, fertile eggs were randomly assigned to five experimental groups comprising (i Fadrozole (0.1 mg/egg, (ii rhIGF-I (100 ng/egg, (iii Fadrozole (0.1 mg/egg + rhIGF-I (100 ng/egg, (iv vehicle injection (10 mM acetic acid and 0.1% BSA, and (v non-injected eggs. Eggs in the rhIGF-I-injected groups showed the mode of hatching time at the 480th hour of incubation, 12 hours earlier compared to the other groups, with no statistically significant difference in mortality and hatchability. On Day 1 and 42 of production, 90% of genetically female chicks were masculinized using Fadrozole treatment, while 100% female-to-male phenotypic sex reversal was observed in the Fadrozole+rhIGF-I group. Fadrozole equalized the body weight of both genders, although rhIGF-I was effective on the body weight of male chicks only. Interestingly, combined rhIGF-I and Fadrozole could increase the body weight in both sexes compared to the individual injections (P<0.05. These findings revealed that (i IGF-I-treated chicken embryos were shown to be an effective option for overcoming the very long chicken deprivation period, (ii the simultaneous treatment with Fadrozole and IGF-I could maximize the female-to-male sex reversal chance, (iii the increase in the body weight of masculinized chickens via Fadrozole could be equal to their genetically male counterparts, and (iv the IGF-I effectiveness, specifically along with the application of aromatase inhibitors in female chicks, indicates that estrogen synthesis could be a stumbling block for the IGF-I action mechanism in female embryos.

  3. 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

  4. A comparative study of age-related hearing loss in wild type and insulin-like growth factor I deficient mice

    Directory of Open Access Journals (Sweden)

    Raquel Riquelme

    2010-06-01

    Full Text Available Insulin-like growth factor-I (IGF-I belongs to the family of insulin-related peptides that fulfils a key role during the late development of the nervous system. Human IGF1 mutations cause profound deafness, poor growth and mental retardation. Accordingly, Igf1−/− null mice are dwarfs that have low survival rates, cochlear alterations and severe sensorineural deafness. Presbycusis (age-related hearing loss is a common disorder associated with aging that causes social and cognitive problems. Aging is also associated with a decrease in circulating IGF-I levels and this reduction has been related to cognitive and brain alterations, although there is no information as yet regarding the relationship between presbycusis and IGF-I biodisponibility. Here we present a longitudinal study of wild type Igf1+/+ and null Igf1−/− mice from 2 to 12 months of age comparing the temporal progression of several parameters: hearing, brain morphology, cochlear cytoarchitecture, insulin-related factors and IGF gene expression and IGF-I serum levels. Complementary invasive and non-invasive techniques were used, including auditory brainstem-evoked response (ABR recordings and in vivo MRI brain imaging. Igf1−/− null mice presented profound deafness at all the ages studied, without any obvious worsening of hearing parameters with aging. Igf1+/+ wild type mice suffered significant age-related hearing loss, their auditory thresholds and peak I latencies augmenting as they aged, in parallel with a decrease in the circulating levels of IGF-I. Accordingly, there was an age-related spiral ganglion degeneration in wild type mice that was not evident in the Igf1 null mice. However, the Igf1−/− null mice in turn developed a prematurely aged stria vascularis reminiscent of the diabetic strial phenotype. Our data indicate that IGF-I is required for the correct development and maintenance of hearing, supporting the idea that IGF-I-based therapies could contribute to

  5. 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 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.

  6. Insulin-like growth factor I (IGF-I) and IGF-binding protein 3 response to growth hormone is impaired in HIV-infected children.

    Science.gov (United States)

    Rondanelli, Mariangela; Caselli, Desiree; Aricò, Maurizio; Maccabruni, Anna; Magnani, Barbara; Bacchella, Luisa; De Stefano, Anna; Maghnie, Mohamed; Solerte, Sebastiano Bruno; Minoli, Lorenzo

    2002-03-20

    To better characterize the somatotropic axis in HIV-infected children the circadian rhythm of growth hormone (GH), and basal and stimulated (by an insulin-like growth factor I [IGF-I] generation test) plasma levels of IGF-I and insulin-like growth factor-binding protein 3 (IGFBP-3), were evaluated in 16 children (9 boys and 7 girls; age range, 7-11 years) with HIV infection. All patients were free from active opportunistic infection or liver disease at the time of the study. Sixteen age- and sex-matched healthy children (10 boys and 6 girls; age range, 7-11 years) served as control subjects. GH rhythmometric data were analyzed by single and population mean cosinor analysis. As regards the IGF-I generation test, biosynthetic human GH (hGH, 0.1 IU/kg, 0.033 mg/kg) was administered subcutaneously for 4 days and blood samples were taken from fasting subjects at baseline and on the morning after the last GH injection for measurement of IGF-I and IGFBP-3. Plasma GH levels fell within normal limits in the HIV-seropositive patients and were similar to those of healthy children (1.31 +/- 1.18 vs. 1.57 +/- 1.16 microg/liter, respectively; mean +/- SD). The population mean cosinor analysis shows that the GH circadian rhythm reached statistical significance both in the HIV-seropositive children and in the control group. Despite this, the IGF-I and IGFBP-3 levels were significantly lower in HIV-infected children than in the control group (75.6 +/- 57.2 vs. 233.3 +/- 52.5 ng/ml, p < 0.001 and 2.09 +/- 0.17 vs. 3.89 +/- 0.24 mg/liter, p < 0.01, respectively; mean +/- SD); moreover, the response of IGF-I and IGFBP-3 to the IGF-I generation test was significantly lower in HIV-infected children than in the control group (86.3 +/- 55.8 vs. 257.5 +/- 53.4 ng/ml, p < 0.001 and 3.14 +/- 0.43 mg/liter, p < 0.01, respectively; mean +/- SD). It appears that circadian GH secretion is normal in children with HIV infection, but the response to exogenous GH with regard to IGF-I and IGFBP-3

  7. Pegvisomant-induced serum insulin-like growth factor-I normalization in patients with acromegaly returns elevated markers of bone turnover to normal

    DEFF Research Database (Denmark)

    Parkinson, C; Kassem, M; Heickendorff, Lene

    2003-01-01

    Active acromegaly is associated with increased biochemical markers of bone turnover. Pegvisomant is a GH receptor antagonist that normalizes serum IGF-I in 97% of patients with active acromegaly. We evaluated the effects of pegvisomant-induced serum IGF-I normalization on biochemical markers...... of bone and soft tissue turnover, as well as levels of PTH and vitamin D metabolites, in 16 patients (nine males; median age, 52 yr; range, 28-78 yr) with active acromegaly (serum IGF-I at least 30% above upper limit of an age-related reference range). Serum procollagen III amino-terminal propeptide...... (PIIINP) and type I procollagen amino-terminal propeptide, osteocalcin (OC), bone-related alkaline phosphatase, C-terminal cross-linked telopeptide of type I collagen (CTx), albumin-corrected calcium, intact PTH, 25-hydroxy vitamin D, 1,25-dihydroxy vitamin D [1,25-(OH)(2) vit D], urinary type 1 collagen...

  8. The (Na(+)/K (+))-ATPase activity in the developing rat retina: the role of insulin-like growth factor-I (IGF-I).

    Science.gov (United States)

    Maturana-Teixeira, Sheila; Braga, Luis Eduardo Gomes; Carpi Santos, Raul; Calaza, Karin da Costa; Giestal-de-Araujo, Elizabeth; Leão-Ferreira, Luiz Roberto

    2015-03-01

    In this work, the (Na(+)/K(+))-ATPase activity was evaluated during the early stages of the postnatal development of rat retina and showed an almost three-time increase from P0 to P14. Expression of the three catalytic subunit isoforms (α1, α2, and α3) of the (Na(+)/K(+))-ATPase was also evaluated by immunoblot in the same period, but no correlation to the catalytic activity increment was observed. On the other hand, immunolocalization of these three α-catalytic isoforms in the developing retina showed an age-related pattern. Involvement of IGF-I in the stimulation of the (Na(+)/K(+))-ATPase was investigated. Our results demonstrate that the exogenous IGF-I (10 ng/mL) stimulates enzyme activity at the age of P7 only. Incubation of retinas with 10 μM I-OMe-AG 538 (inhibitor of the IGF-I receptor) indicates that the basal (Na(+)/K(+))-ATPase activity is sustained by endogenous IGF-I in P7 animals. These data were corroborated by an age-dependent decrease in the immunodetection of endogenous IGF-I as well as in the phosphorylation level of its cognate receptor in rat retina homogenates. The signaling pathway involved in IGF-I-induced modulation of the (Na(+)/K(+))-ATPase was also investigated. Our data show that the inhibitory effects induced by I-OMe-AG 538 and the PI 3-kinase inhibitor Ly 294002 on the basal (Na(+)/K(+))-ATPase activity were non-cumulative. Furthermore, IGF-I induced phosphorylation of PKB in a Ly 294002-sensitive manner. Together, these data demonstrate that the PI 3-kinase/PKB signaling pathway is involved in the IGF-I-sustained basal (Na(+)/K(+))-ATPase activity during the first 7 days of the postnatal development of rat retina.

  9. AMPA receptor ligands

    DEFF Research Database (Denmark)

    Strømgaard, Kristian; Mellor, Ian

    2004-01-01

    Alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors (AMPAR), subtype of the ionotropic glutamate receptors (IGRs), mediate fast synaptic transmission in the central nervous system (CNS), and are involved in many neurological disorders, as well as being a key player...

  10. Angiotensin type 2 receptors

    DEFF Research Database (Denmark)

    Sumners, Colin; de Kloet, Annette D; Krause, Eric G

    2015-01-01

    In most situations, the angiotensin AT2-receptor (AT2R) mediates physiological actions opposing those mediated by the AT1-receptor (AT1R), including a vasorelaxant effect. Nevertheless, experimental evidence vastly supports that systemic application of AT2R-agonists is blood pressure neutral...

  11. Glutamate receptor agonists

    DEFF Research Database (Denmark)

    Vogensen, Stine Byskov; Greenwood, Jeremy R; Bunch, Lennart

    2011-01-01

    The neurotransmitter (S)-glutamate [(S)-Glu] is responsible for most of the excitatory neurotransmission in the central nervous system. The effect of (S)-Glu is mediated by both ionotropic and metabotropic receptors. Glutamate receptor agonists are generally a-amino acids with one or more...... stereogenic centers due to strict requirements in the agonist binding pocket of the activated state of the receptor. By contrast, there are many examples of achiral competitive antagonists. The present review addresses how stereochemistry affects the activity of glutamate receptor ligands. The review focuses...... mainly on agonists and discusses stereochemical and conformational considerations as well as biostructural knowledge of the agonist binding pockets, which is useful in the design of glutamate receptor agonists. Examples are chosen to demonstrate how stereochemistry not only determines how the agonist...

  12. The interactions between hypothalamic-pituitary-adrenal axis activity, testosterone, insulin-like growth factor I and abdominal obesity with metabolism and blood pressure in men.

    Science.gov (United States)

    Rosmond, R; Björntorp, P

    1998-12-01

    To examine potential interactions between abdominal obesity, endocrine, metabolic and hemodynamic perturbations. A subgroup of 284 men from a population sample of 1040 at the age of 51 y. Anthropometric measurements included body mass index (BMI, kg/m2), waist/hip circumference ratio (WHR) and abdominal sagittal diameter (D). Endocrine measurements were a modified, low dose (0.5 mg) dexamethasone suppression test (Dex), testosterone (T) and insulin-like growth factor I (IGF-I). Overnight fasting values of blood glucose, serum insulin, triglycerides, total, low and high density lipoprotein cholesterol, as well as resting heart rate and blood pressure were also determined. Arbitrary subdivisions of the men were performed to obtain subgroups of low T and IGF-I values (lowest decile, borderlines low density lipoprotein cholesterol, were then found in subgroups with different endocrine profiles. These included men with a blunted Dex test with low T or IGF-I values, as well as men with a normal Dex test and low or normal T or IGF-I values. In addition, a group with isolated low Dex suppression, as well as another group without endocrine abnormalities, showed such relationships. These findings suggest that, in men, obesity factors are associated with metabolic and hemodynamic complications with or without the presence of perturbations of hypothalamic-pituitary-adrenal axis (HPA) regulation or low T or growth hormone secretion. In order to generate hypotheses concerning the nature of the impact of the endocrine perturbations in abdominal obesity and its metabolic complications, path analyses were performed, testing different models. These models included the endocrine measurements (Dex test, T and IGF-I), the WHR and D (representing abdominal distribution of fat), BMI (representing obesity), as well as insulin and triglyceride values (representing metabolic perturbations). The results showed a satisfactory fit (goodness-of-fit index: 0.945 - 1.0) for the path diagrams: Dex

  13. P2X receptors.

    Science.gov (United States)

    North, R Alan

    2016-08-05

    Extracellular adenosine 5'-triphosphate (ATP) activates cell surface P2X and P2Y receptors. P2X receptors are membrane ion channels preferably permeable to sodium, potassium and calcium that open within milliseconds of the binding of ATP. In molecular architecture, they form a unique structural family. The receptor is a trimer, the binding of ATP between subunits causes them to flex together within the ectodomain and separate in the membrane-spanning region so as to open a central channel. P2X receptors have a widespread tissue distribution. On some smooth muscle cells, P2X receptors mediate the fast excitatory junction potential that leads to depolarization and contraction. In the central nervous system, activation of P2X receptors allows calcium to enter neurons and this can evoke slower neuromodulatory responses such as the trafficking of receptors for the neurotransmitter glutamate. In primary afferent nerves, P2X receptors are critical for the initiation of action potentials when they respond to ATP released from sensory cells such as taste buds, chemoreceptors or urothelium. In immune cells, activation of P2X receptors triggers the release of pro-inflammatory cytokines such as interleukin 1β. The development of selective blockers of different P2X receptors has led to clinical trials of their effectiveness in the management of cough, pain, inflammation and certain neurodegenerative diseases.This article is part of the themed issue 'Evolution brings Ca(2+) and ATP together to control life and death'. © 2016 The Author(s).

  14. Growth hormone receptor gene expression in puberty.

    Science.gov (United States)

    Pagani, S; Meazza, C; Gertosio, C; Bozzola, E; Bozzola, M

    2015-07-01

    The mechanisms regulating the synergic effect of growth hormone and other hormones during pubertal spurt are not completely clarified. We enrolled 64 females of Caucasian origin and normal height including 22 prepubertal girls, 26 pubertal girls, and 16 adults to evaluate the role of Growth Hormone/Insulin-like growth factor-I axis (GH/IGF-I) during the pubertal period. In these subjects both serum IGF-I and growth hormone binding protein levels, as well as quantitative growth hormone receptor (GHR) gene expression were evaluated in peripheral lymphocytes of all individuals by real-time PCR. Our results showed significantly lower IGF-I levels in women (148±10 ng/ml) and prepubertal girls (166.34±18.85 ng/ml) compared to pubertal girls (441.95±29.42 ng/ml; p<0.0001). Serum GHBP levels were significantly higher in prepubertal (127.02±20.76 ng/ml) compared to pubertal girls (16.63±2.97 ng/ml; p=0.0001) and adult women (19.95±6.65 ng/ml; p=0.0003). We also found higher GHR gene expression levels in pubertal girls [174.73±80.22 ag (growth hormone receptor)/5×10(5) ag (glyceraldehyde 3-phosphate dehydrogenase)] compared with other groups of subjects [women: 42.52±7.66 ag (growth hormone receptor)/5×10(5) ag (glyceraldehyde 3-phosphate dehydrogenase); prepubertal girls: 58.45±0.18.12 ag (growth hormone receptor)/5×10(5) ag (glyceraldehyde 3-phosphate dehydrogenase)], but the difference did not reach statistical significance. These results suggest that sexual hormones could positively influence GHR action, during the pubertal period, in a dual mode, that is, increasing GHR mRNA production and reducing GHR cleavage leading to GHBP variations. © Georg Thieme Verlag KG Stuttgart · New York.

  15. Muscarinic receptor oligomerization.

    Science.gov (United States)

    Marsango, Sara; Ward, Richard J; Alvarez-Curto, Elisa; Milligan, Graeme

    2017-11-14

    G protein-coupled receptors (GPCRs) have been classically described as monomeric entities that function by binding in a 1:1 stoichiometric ratio to both ligand and downstream signalling proteins. However, in recent years, a growing number of studies has supported the hypothesis that these receptors can interact to form dimers and higher order oligomers although the molecular basis for these interactions, the overall quaternary arrangements and the functional importance of GPCR oligomerization remain topics of intense speculation. Muscarinic acetylcholine receptors belong to class A of the GPCR family. Each muscarinic receptor subtype has its own particular distribution throughout the central and peripheral nervous systems. In the central nervous system, muscarinic receptors regulate several sensory, cognitive, and motor functions while, in the peripheral nervous system, they are involved in the regulation of heart rate, stimulation of glandular secretion and smooth muscle contraction. Muscarinic acetylcholine receptors have long been used as a model for the study of GPCR structure and function and to address aspects of GPCR dimerization using a broad range of approaches. In this review, the prevailing knowledge regarding the quaternary arrangement for the various muscarinic acetylcholine receptors has been summarized by discussing work ranging from initial results obtained using more traditional biochemical approaches to those generated with more modern biophysical techniques. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

  16. 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

  17. Glutamate receptor agonists

    DEFF Research Database (Denmark)

    Vogensen, Stine Byskov; Greenwood, Jeremy R; Bunch, Lennart

    2011-01-01

    stereogenic centers due to strict requirements in the agonist binding pocket of the activated state of the receptor. By contrast, there are many examples of achiral competitive antagonists. The present review addresses how stereochemistry affects the activity of glutamate receptor ligands. The review focuses...... mainly on agonists and discusses stereochemical and conformational considerations as well as biostructural knowledge of the agonist binding pockets, which is useful in the design of glutamate receptor agonists. Examples are chosen to demonstrate how stereochemistry not only determines how the agonist...

  18. P2X receptors

    OpenAIRE

    North, R. Alan

    2016-01-01

    Extracellular adenosine 5′-triphosphate (ATP) activates cell surface P2X and P2Y receptors. P2X receptors are membrane ion channels preferably permeable to sodium, potassium and calcium that open within milliseconds of the binding of ATP. In molecular architecture, they form a unique structural family. The receptor is a trimer, the binding of ATP between subunits causes them to flex together within the ectodomain and separate in the membrane-spanning region so as to open a central channel. P2...

  19. Serotonin Receptors in Hippocampus

    Science.gov (United States)

    Berumen, Laura Cristina; Rodríguez, Angelina; Miledi, Ricardo; García-Alcocer, Guadalupe

    2012-01-01

    Serotonin is an ancient molecular signal and a recognized neurotransmitter brainwide distributed with particular presence in hippocampus. Almost all serotonin receptor subtypes are expressed in hippocampus, which implicates an intricate modulating system, considering that they can be localized as autosynaptic, presynaptic, and postsynaptic receptors, even colocalized within the same cell and being target of homo- and heterodimerization. Neurons and glia, including immune cells, integrate a functional network that uses several serotonin receptors to regulate their roles in this particular part of the limbic system. PMID:22629209

  20. Influence of ad libitum milk replacer feeding and butyrate supplementation on the systemic and hepatic insulin-like growth factor I and its binding proteins in Holstein calves.

    Science.gov (United States)

    Frieten, D; Gerbert, C; Koch, C; Dusel, G; Eder, K; Hoeflich, A; Mielenz, B; Hammon, H M

    2018-02-01

    Ad libitum milk feeding and butyrate (B) supplementation have the potential to stimulate postnatal growth and development in calves. The somatotropic axis is the main endocrine regulator of postnatal growth and may be affected by both ad libitum milk replacer (MR) feeding and B supplementation in calves. We hypothesized that ad libitum MR feeding and B supplementation stimulate systemic and hepatic insulin-like growth factor (IGF)-I and IGF binding proteins (IGFBP) in preweaning calves. Sixty-four (32 male, 32 female) Holstein calves were examined from birth until wk 11 of life. Calves received MR either ad libitum (Adl) or restrictively (6 L/d; Res). In each feeding group half of the calves received a MR with 0.24% butyrate and the other half received same MR without butyrate. Ad libitum MR feeding was performed from d 4 until wk 8 of age. From wk 9 to 10, Adl and Res calves were gradually weaned and were fed 2 L/d until the end of the trial. Concentrate, hay, and water were freely available. Feed intake was measured daily and body weight weekly. Blood samples for analyzing plasma concentrations of glucose, insulin, IGF-I, and IGFBP-2, -3, and -4 were taken on d 1, 2, 4, and 7, then weekly or every other week (IGFBP) until wk 11 of life. Liver samples were taken on d 50 and at the end of the study (d 80) to measure gene expression of the growth hormone receptor 1A (GHR1A), IGF1, IGFBP1 to 4, and of the IGF Type 1 and insulin receptor in the liver. Intake of MR and body weight were greater, but concentrate intake was lower in Adl than in Res. Plasma concentrations of IGF-I and IGFBP-3 were greater and plasma concentration of IGFBP-2 was lower in Adl than in Res during the ad libitum milk feeding period. After reduction of MR in both groups to 2 L/d plasma concentrations of IGF-I and IGFBP-4 were lower and plasma concentration of IGFBP-2 was higher in Adl than in Res. Supplementation of B depressed plasma IGF-I from wk 1 to 4 and in wk 9. On d 50, mRNA abundance of

  1. Somatostatin receptor skintigrafi

    DEFF Research Database (Denmark)

    Rasmussen, Karin; Nielsen, Jørn Theil; Rehling, Michael

    2005-01-01

    Somatostatin receptor scintigraphy (SRS) is a very valuable imaging technique for visualisation of a diversity of neuroendocrine tumours. The sensitivity for localisation of carcinoid tumours is high, but somewhat lower for other neuroendocrine tumours. The methodology, multiple clinical aspects ...

  2. Muscarinic receptor oligomerization

    OpenAIRE

    Marsango, Sara; Ward, Richard J.; Alvarez-Curto, Elisa; Milligan, Graeme

    2017-01-01

    G protein-coupled receptors (GPCRs) have been classically described as monomeric entities that function by binding in a 1:1 stoichiometric ratio to both ligand and downstream signalling proteins. However, in recent years, a growing number of studies has supported the hypothesis that these receptors can interact to form dimers and higher order oligomers although the molecular basis for these interactions, the overall quaternary arrangements and the functional importance of GPCR oligomerization...

  3. Endocrine systems in juvenile anadromous and landlocked Atlantic salmon (Salmo salar): Seasonal development and seawater acclimation

    Science.gov (United States)

    Nilsen, Tom O.; Ebbesson, Lars O.E.; Kiilerich, P.; Bjornsson, B. Th; Madsen, Steffen S.; McCormick, S.D.; Stefansson, S.O.

    2008-01-01

    The present study compares developmental changes in plasma levels of growth hormone (GH), insulin-like growth factor I (IGF-I) and cortisol, and mRNA levels of their receptors and the prolactin receptor (PRLR) in the gill of anadromous and landlocked Atlantic salmon during the spring parr-smolt transformation (smoltification) period and following four days and one month seawater (SW) acclimation. Plasma GH and gill GH receptor (GHR) mRNA levels increased continuously during the spring smoltification period in the anadromous, but not in landlocked salmon. There were no differences in plasma IGF-I levels between strains, or any increase during smoltification. Gill IGF-I and IGF-I receptor (IGF-IR) mRNA levels increased in anadromous salmon during smoltification, with no changes observed in landlocked fish. Gill PRLR mRNA levels remained stable in both strains during spring. Plasma cortisol levels in anadromous salmon increased 5-fold in May and June, but not in landlocked salmon. Gill glucocorticoid receptor (GR) mRNA levels were elevated in both strains at the time of peak smoltification in anadromous salmon, while mineralocorticoid receptor (MR) mRNA levels remained stable. Only anadromous salmon showed an increase of gill 11??-hydroxysteroid dehydrogenase type-2 (11??-HSD2) mRNA levels in May. GH and gill GHR mRNA levels increased in both strains following four days of SW exposure in mid-May, whereas only the anadromous salmon displayed elevated plasma GH and GHR mRNA after one month in SW. Plasma IGF-I increased after four days in SW in both strains, decreasing in both strains after one month in SW. Gill IGF-I mRNA levels were only increased in landlocked salmon after 4 days in SW. Gill IGF-IR mRNA levels in SW did not differ from FW levels in either strain. Gill PRLR mRNA did not change after four days of SW exposure, and decreased in both strains after one month in SW. Plasma cortisol levels did not change following SW exposure in either strain. Gill GR, 11

  4. Adenosine receptor neurobiology: overview.

    Science.gov (United States)

    Chen, Jiang-Fan; Lee, Chien-fei; Chern, Yijuang

    2014-01-01

    Adenosine is a naturally occurring nucleoside that is distributed ubiquitously throughout the body as a metabolic intermediary. In the brain, adenosine functions as an important upstream neuromodulator of a broad spectrum of neurotransmitters, receptors, and signaling pathways. By acting through four G-protein-coupled receptors, adenosine contributes critically to homeostasis and neuromodulatory control of a variety of normal and abnormal brain functions, ranging from synaptic plasticity, to cognition, to sleep, to motor activity to neuroinflammation, and cell death. This review begun with an overview of the gene and genome structure and the expression pattern of adenosine receptors (ARs). We feature several new developments over the past decade in our understanding of AR functions in the brain, with special focus on the identification and characterization of canonical and noncanonical signaling pathways of ARs. We provide an update on functional insights from complementary genetic-knockout and pharmacological studies on the AR control of various brain functions. We also highlight several novel and recent developments of AR neurobiology, including (i) recent breakthrough in high resolution of three-dimension structure of adenosine A2A receptors (A2ARs) in several functional status, (ii) receptor-receptor heterodimerization, (iii) AR function in glial cells, and (iv) the druggability of AR. We concluded the review with the contention that these new developments extend and strengthen the support for A1 and A2ARs in brain as therapeutic targets for neurologic and psychiatric diseases. © 2014 Elsevier Inc. All rights reserved.

  5. Genetics of taste receptors.

    Science.gov (United States)

    Bachmanov, Alexander A; Bosak, Natalia P; Lin, Cailu; Matsumoto, Ichiro; Ohmoto, Makoto; Reed, Danielle R; Nelson, Theodore M

    2014-01-01

    Taste receptors function as one of the interfaces between internal and external milieus. Taste receptors for sweet and umami (T1R [taste receptor, type 1]), bitter (T2R [taste receptor, type 2]), and salty (ENaC [epithelial sodium channel]) have been discovered in the recent years, but transduction mechanisms of sour taste and ENaC-independent salt taste are still poorly understood. In addition to these five main taste qualities, the taste system detects such noncanonical "tastes" as water, fat, and complex carbohydrates, but their reception mechanisms require further research. Variations in taste receptor genes between and within vertebrate species contribute to individual and species differences in taste-related behaviors. These variations are shaped by evolutionary forces and reflect species adaptations to their chemical environments and feeding ecology. Principles of drug discovery can be applied to taste receptors as targets in order to develop novel taste compounds to satisfy demand in better artificial sweeteners, enhancers of sugar and sodium taste, and blockers of bitterness of food ingredients and oral medications.

  6. Ionotropic crustacean olfactory receptors.

    Directory of Open Access Journals (Sweden)

    Elizabeth A Corey

    Full Text Available The nature of the olfactory receptor in crustaceans, a major group of arthropods, has remained elusive. We report that spiny lobsters, Panulirus argus, express ionotropic receptors (IRs, the insect chemosensory variants of ionotropic glutamate receptors. Unlike insects IRs, which are expressed in a specific subset of olfactory cells, two lobster IR subunits are expressed in most, if not all, lobster olfactory receptor neurons (ORNs, as confirmed by antibody labeling and in situ hybridization. Ligand-specific ORN responses visualized by calcium imaging are consistent with a restricted expression pattern found for other potential subunits, suggesting that cell-specific expression of uncommon IR subunits determines the ligand sensitivity of individual cells. IRs are the only type of olfactory receptor that we have detected in spiny lobster olfactory tissue, suggesting that they likely mediate olfactory signaling. Given long-standing evidence for G protein-mediated signaling in activation of lobster ORNs, this finding raises the interesting specter that IRs act in concert with second messenger-mediated signaling.

  7. Effect of iron deficiency on the expression of insulin-like growth factor-II and its receptor in neuronal and glial cells.

    Science.gov (United States)

    Morales González, E; Contreras, I; Estrada, J A

    2014-09-01

    Many studies have demonstrated that iron deficiency modifies the normal function of the central nervous system and alters cognitive abilities. When cellular damage occurs in the central nervous system, neuroprotective mechanisms, such as the production of neurotrophic factors, are essential in order for nervous tissue to function correctly. Insulin-like growth factor II (IGF- II) is a neurotrophic factor that was recently shown to be involved in the normal functioning of cognitive processes in animal models. However, the impact of iron deficiency on the expression and function of this molecule has not yet been clarified. Mixed primary cell cultures from the central nervous system were collected to simulate iron deficiency using deferoxamine. The expression of IGF-I, IGF-II, IGF-IR, and IGF-IIR was determined with the western blot test. We observed increased expression of IGF-II, along with a corresponding decrease in the expression of IGF-IIR, in iron-deficient mixed primary cell cultures. We did not observe alterations in the expression of these proteins in isolated microglia or neuronal cultures under the same conditions. We did not detect differences in the expression of IGF-I and IGF-IR in iron-deficient cultures. In vitro iron deficiency increases the expression of IGF-II in mixed glial cell cultures, which may have a beneficial effect on brain tissue homeostasis in a situation in which iron availability is decreased. Copyright © 2013 Sociedad Española de Neurología. Published by Elsevier Espana. All rights reserved.

  8. Characterization of a second ligand binding site of the insulin receptor

    International Nuclear Information System (INIS)

    Hao Caili; Whittaker, Linda; Whittaker, Jonathan

    2006-01-01

    Insulin binding to its receptor is characterized by high affinity, curvilinear Scatchard plots, and negative cooperativity. These properties may be the consequence of binding of insulin to two receptor binding sites. The N-terminal L1 domain and the C-terminus of the α subunit contain one binding site. To locate a second site, we examined the binding properties of chimeric receptors in which the L1 and L2 domains and the first Fibronectin Type III repeat of the insulin-like growth factor-I receptor were replaced by corresponding regions of the insulin receptor. Substitutions of the L2 domain and the first Fibronectin Type III repeat together with the L1 domain produced 80- and 300-fold increases in affinity for insulin. Fusion of these domains to human immunoglobulin Fc fragment produced a protein which bound insulin with a K d of 2.9 nM. These data strongly suggest that these domains contain an insulin binding site

  9. adrenergic receptor with preeclampsia

    African Journals Online (AJOL)

    User

    2011-05-09

    May 9, 2011 ... expenditure and lipolysis. The mechanisms underlying lipolytic resistance to catecholamines in obesity are not clear and may include desensitization of ADRB2 function. (Yamada et al., 1999). Many studies have reported on the relationship between obesity and genetic variants in β-2 adrenergic receptors ...

  10. Ginkgolides and glycine receptors

    DEFF Research Database (Denmark)

    Jaracz, Stanislav; Nakanishi, Koji; Jensen, Anders A.

    2004-01-01

    Ginkgolides from the Ginkgo biloba tree are diterpenes with a cage structure consisting of six five-membered rings and a unique tBu group. They exert a variety of biological properties. In addition to being antagonists of the platelet activating factor receptor (PAFR), it has recently been shown ...

  11. Meeting report: nuclear receptors

    DEFF Research Database (Denmark)

    Tuckermann, Jan; Bourguet, William; Mandrup, Susanne

    2010-01-01

    The biannual European Molecular Biology Organization (EMBO) conference on nuclear receptors was organized by Beatrice Desvergne and Laszlo Nagy and took place in Cavtat near Dubrovnik on the Adriatic coast of Croatia September 25-29, 2009. The meeting brought together researchers from all over...

  12. Metformin and insulin receptors

    International Nuclear Information System (INIS)

    Vigneri, R.; Gullo, D.; Pezzino, V.

    1984-01-01

    The authors evaluated the effect of metformin (N,N-dimethylbiguanide), a biguanide known to be less toxic than phenformin, on insulin binding to its receptors, both in vitro and in vivo. Specific 125 I-insulin binding to cultured IM-9 human lymphocytes and MCF-7 human breast cancer cells was determined after preincubation with metformin. Specific 125 I-insulin binding to circulating monocytes was also evaluated in six controls, eight obese subjects, and six obese type II diabetic patients before and after a short-term treatment with metformin. Plasma insulin levels and blood glucose were also measured on both occasions. Metformin significantly increased insulin binding in vitro to both IM-9 lymphocytes and MCF-7 cells; the maximum increment was 47.1% and 38.0%, respectively. Metformin treatment significantly increased insulin binding in vivo to monocytes of obese subjects and diabetic patients. Scatchard analysis indicated that the increased binding was mainly due to an increase in receptor capacity. Insulin binding to monocytes of normal controls was unchanged after metformin as were insulin levels in all groups; blood glucose was significantly reduced after metformin only in diabetic patients. These data indicate that metformin increases insulin binding to its receptors in vitro and in vivo. The effect in vivo is observed in obese subjects and in obese type II diabetic patients, paralleling the clinical effectiveness of this antidiabetic agent, and is not due to receptor regulation by circulating insulin, since no variation in insulin levels was recorded

  13. Angiotensin type 2 receptor (AT2R) and receptor Mas

    DEFF Research Database (Denmark)

    Villela, Daniel; Leonhardt, Julia; Patel, Neal

    2015-01-01

    The angiotensin type 2 receptor (AT2R) and the receptor Mas are components of the protective arms of the renin-angiotensin system (RAS), i.e. they both mediate tissue protective and regenerative actions. The spectrum of actions of these two receptors and their signalling mechanisms display striking...... the phenomenon of blockade of angiotensin-(1-7) [Ang-(1-7)] actions by AT2R antagonists and vice versa. Such mechanisms may comprise dimerization of the receptors or dimerization-independent mechanisms such as lack of specificity of the receptor ligands used in the experiments or involvement of the Ang-(1...

  14. Prostaglandin Receptor Signaling in Disease

    Directory of Open Access Journals (Sweden)

    Toshiyuki Matsuoka

    2007-01-01

    Full Text Available Prostanoids, consisting of the prostaglandins (PGs and the thromboxanes (TXs, are a group of lipid mediators formed in response to various stimuli. They include PGD2, PGE2, PGF2α, PGI2, and TXA2. They are released outside of the cells immediately after synthesis, and exert their actions by binding to a G-protein coupled rhodopsin-type receptor on the surface of target cells. There are eight types of the prostanoid receptors conserved in mammals from mouse to human. They are the PGD receptor (DP, four subtypes of the PGE receptor (EP1, EP2, EP3, and EP4, the PGF receptor (FP, PGI receptor (IP, and TXA receptor (TP. Recently, mice deficient in each of these prostanoid receptors were generated and subjected to various experimental models of disease. These studies have revealed the roles of PG receptor signaling in various pathological conditions, and suggest that selective manipulation of the prostanoid receptors may be beneficial in treatment of the pathological conditions. Here we review these recent findings of roles of prostanoid receptor signaling and their therapeutic implications.

  15. Receptors for enterovirus 71.

    Science.gov (United States)

    Yamayoshi, Seiya; Fujii, Ken; Koike, Satoshi

    2014-07-01

    Enterovirus 71 (EV71) is one of the major causative agents of hand, foot and mouth disease (HFMD). Occasionally, EV71 infection is associated with severe neurological diseases, such as acute encephalitis, acute flaccid paralysis and cardiopulmonary failure. Several molecules act as cell surface receptors that stimulate EV71 infection, including scavenger receptor B2 (SCARB2), P-selectin glycoprotein ligand-1 (PSGL-1), sialylated glycan, heparan sulfate and annexin II (Anx2). SCARB2 plays critical roles in attachment, viral entry and uncoating, and it can facilitate efficient EV71 infection. The three-dimensional structures of the mature EV71 virion, procapsid and empty capsid, as well as the exofacial domain of SCARB2, have been elucidated. This structural information has greatly increased our understanding of the early steps of EV71 infection. Furthermore, SCARB2 plays essential roles in the development of EV71 neurological disease in vivo. Adult mice are not susceptible to infection by EV71, but transgenic mice that express human SCARB2 become susceptible to EV71 infection and develop similar neurological diseases to those found in humans. This mouse model facilitates the in vivo investigation of many issues related to EV71. PSGL-1, sialylated glycan, heparan sulfate and Anx2 are attachment receptors, which enhance viral infection by retaining the virus on the cell surface. These molecules also contribute to viral infection in vitro either by interacting with SCARB2 or independently of SCARB2. However, the cooperative effects of these receptors, and their contribution to EV71 pathogenicity in vivo, remain to be elucidated.

  16. The interleukin-4 receptor: signal transduction by a hematopoietin receptor.

    Science.gov (United States)

    Keegan, A D; Pierce, J H

    1994-02-01

    Over the last several years, the receptors for numerous cytokines have been molecularly characterized. Analysis of their amino acid sequences shows that some of these receptors bear certain motifs in their extracellular domains that define a family of receptors called the Hematopoietin receptor superfamily. Significant advances in characterizing the structure, function, and mechanisms of signal transduction have been made for several members of this family. The purpose of this review is to discuss the recent advances made for one of the family members, the interleukin (IL) 4 receptor. Other receptor systems have recently been reviewed elsewhere. The IL-4 receptor consists of, at the minimum, the cloned 140 kDa IL-4-binding chain with the potential for associating with other chains. The IL-4 receptor transduces its signal by activating a tyrosine kinase that phosphorylates cellular substrates, including the receptor itself, and the 170 kDa substrate called 4PS. Phosphorylated 4PS interacts with the SH2 domain of the enzyme PI-3'-kinase and increases its enzymatic activity. These early events in the IL-4 receptor initiated signaling pathway may trigger a series of signals that will ultimately lead to an IL-4 specific biologic outcome.

  17. Evolutionary analysis of functional divergence among chemokine receptors, decoy receptors and viral receptors

    Directory of Open Access Journals (Sweden)

    Hiromi eDaiyasu

    2012-07-01

    Full Text Available Chemokine receptors (CKRs function in the inflammatory response and in vertebrate homeostasis. Decoy and viral receptors are two types of CKR homologues with modified functions from those of the typical CKRs. The decoy receptors are able to bind ligands without signaling. On the other hand, the viral receptors show constitutive signaling without ligands. We examined the sites related to the functional difference. At first, the decoy and viral receptors were each classified into five groups, based on the molecular phylogenetic analysis. A multiple amino acid sequence alignment between each group and the CKRs was then constructed. The difference in the amino acid composition between the group and the CKRs was evaluated as the Kullback-Leibler (KL information value at each alignment site. The KL information value is considered to reflect the difference in the functional constraints at the site. The sites with the top 5% of KL information values were selected and mapped on the structure of a CKR. The comparisons with decoy receptor groups revealed that the detected sites were biased on the intracellular side. In contrast, the sites detected from the comparisons with viral receptor groups were found on both the extracellular and intracellular sides. More sites were found in the ligand-binding pocket in the analyses of the viral receptor groups, as compared to the decoy receptor groups. Some of the detected sites were located in the GPCR motifs. For example, the DRY motif of the decoy receptors was often degraded, although the motif of the viral receptors was basically conserved. The observations for the viral receptor groups suggested that the constraints in the pocket region are loose and that the sites on the intracellular side are different from those for the decoy receptors, which may be related to the constitutive signaling activity of the viral receptors.

  18. Melatonin Receptor Genes in Vertebrates

    Directory of Open Access Journals (Sweden)

    Hua Dong Yin

    2013-05-01

    Full Text Available Melatonin receptors are members of the G protein-coupled receptor (GPCR family. Three genes for melatonin receptors have been cloned. The MT1 (or Mel1a or MTNR1A and MT2 (or Mel1b or MTNR1B receptor subtypes are present in humans and other mammals, while an additional melatonin receptor subtype, Mel1c (or MTNR1C, has been identified in fish, amphibians and birds. Another melatonin related orphan receptor, GPR50, which does not bind melatonin, is found exclusively in mammals. The hormone melatonin is secreted primarily by the pineal gland, with highest levels occurring during the dark period of a circadian cycle. This hormone acts systemically in numerous organs. In the brain, it is involved in the regulation of various neural and endocrine processes, and it readjusts the circadian pacemaker, the suprachiasmatic nucleus. This article reviews recent studies of gene organization, expression, evolution and mutations of melatonin receptor genes of vertebrates. Gene polymorphisms reveal that numerous mutations are associated with diseases and disorders. The phylogenetic analysis of receptor genes indicates that GPR50 is an outgroup to all other melatonin receptor sequences. GPR50 may have separated from a melatonin receptor ancestor before the split between MTNR1C and the MTNR1A/B ancestor.

  19. Sustained low-dose growth hormone therapy optimizes bioactive insulin-like growth factor-I level and may enhance CD4 T-cell number in HIV infection

    DEFF Research Database (Denmark)

    Andersen, Ove; Hansen, Birgitte Rønde; Troensegaard, William

    2010-01-01

    expedient IGF-I levels and improve CD4 T-cell response. Total and free IGF-I increased at week 36 (+97%, P CD4 T-cell number increased at week 36...... (+15%, P cells/microL). Following rhGH dose reduction, total IGF-I and CD4 T-cell number remained increased at week 88 (+44%, P = 0.01 and +33%, P ...High-dose recombinant human growth hormone (rhGH) (2-6 mg/day) regimes may facilitate T-cell restoration in patients infected with human immunodeficiency virus (HIV) on highly active antiretroviral therapy (HAART). However, high-dose rhGH regimens increase insulin-like growth factor-I (IGF...

  20. Genetics Home Reference: complement factor I deficiency

    Science.gov (United States)

    ... I deficiency: evaluation of three generations of a Brazilian family. Clin Exp Immunol. 2006 Feb;143(2): ... should consult with a qualified healthcare professional . About Selection Criteria for Links Data Files & API Site Map ...

  1. Flavivirus Entry Receptors: An Update

    Directory of Open Access Journals (Sweden)

    Manuel Perera-Lecoin

    2013-12-01

    Full Text Available Flaviviruses enter host cells by endocytosis initiated when the virus particles interact with cell surface receptors. The current model suggests that flaviviruses use at least two different sets of molecules for infectious entry: attachment factors that concentrate and/or recruit viruses on the cell surface and primary receptor(s that bind to virions and direct them to the endocytic pathway. Here, we present the currently available knowledge regarding the flavivirus receptors described so far with specific attention to C-type lectin receptors and the phosphatidylserine receptors, T-cell immunoglobulin and mucin domain (TIM and TYRO3, AXL and MER (TAM. Their role in flavivirus attachment and entry as well as their implication in the virus biology will be discussed in depth.

  2. Distribution of IGF receptors in the plasma membrane of proximal tubular cells

    International Nuclear Information System (INIS)

    Hammerman, M.R.; Rogers, S.

    1987-01-01

    To characterize the distribution of receptors for insulin-like growth factors I and II (IGF I and II) in the plasma membrane of the renal proximal tubular cell, the authors measured binding of 125 I-labeled IGF I and 125 I-labeled IGF II to proximal tubular basolateral and brush-border membranes and characterized IGF I-stimulated phosphorylation of detergent-solubilized membranes. 125 I-IGF bound primarily to a 135,000 relative molecular weight (M r ) protein and IGF II to a 260,000 M r protein in isolated membranes. Binding of 125 I-IGF I was severalfold greater in basolateral than in brush-border membranes. IGF I-stimulated phosphorylation of the 92,000 M r β-subunit of its receptors could be demonstrated only in basolateral membranes. These findings are consistent with an asymmetrical distribution of receptors for IGF I in the plasma membrane of the renal proximal tubular cell, localization being primary on the basolateral side. In contrast, binding of 125 I-IGF II to isolated basolateral and brush-border membranes was equivalent, suggesting that receptors for this peptide are distributed more symmetrically in the plasma membrane. The findings suggest that the action of IGF I in proximal tubule are mediated via interaction of circulating peptide with specific receptors in the basolateral membrane. However, the findings established the potential for actions of IGF II to be exerted in proximal tubule via interaction with both basolateral and/or brush-border membrane receptors

  3. Dimerization of nuclear receptors.

    Science.gov (United States)

    Germain, Pierre; Bourguet, William

    2013-01-01

    Multicellular organisms require specific intercellular communication to properly organize the complex body plan during embryogenesis and maintain its properties and functions during the entire life. While growth factors, neurotransmitters, and peptide hormones bind to membrane receptors, thereby inducing the activity of intracellular kinase cascades or the JAK-STAT signaling pathways, other small signaling compounds such as steroid hormones, certain vitamins, and metabolic intermediates enter, or are generated, within the target cells and bind to members of a large family of nuclear receptors (NRs). NRs are ligand-inducible transcription factors that control a plethora of biological phenomena, thus orchestrating complex events like development, organ homeostasis, immune function, and reproduction. NR-NR interactions are of major importance in these regulatory processes, as NRs regulate their target genes by binding to cognate DNA response elements essentially as homo- or heterodimers. A number of structural and functional studies have provided significant insights as to how combinatorial NRs rely on protein-protein contacts that discriminate geometric features of their DNA response elements, thereby allowing both binding site diversity and physiological specificity. Here, we will review our current understanding of NR-NR interactions and provide protocols for a number of experimental approaches that are useful for their study. Copyright © 2013 Elsevier Inc. All rights reserved.

  4. Receptor studies in biological psychiatry

    International Nuclear Information System (INIS)

    Fujiwara, Yutaka

    1992-01-01

    Recent advances in the pharmacological treatment of endogenous psychosis have led to the development of biological studies in psychiatry. Studies on neurotransmitter receptors were reviewed in order to apply positron-emission tomograph (PET) for biological psychiatry. The dopamine (DA) hypothesis for schizophrenia was advanced on the basis of the observed effects of neuroleptics and methamphetamine, and DA(D 2 ) receptor supersensitivity measured by PET and receptor binding in the schizophrenic brain. The clinical potencies of neuroleptics for schizophrenia were correlated with their abilities to inhibit the D 2 receptor, and not other receptors. The σ receptor was expected to be a site of antipsychotic action. However, the potency of drugs action on it was not correlated with clinical efficacy. Haloperidol binds with high affinity to the σ receptor, which may mediate acute dystonia, an extrapyramidal side effect of neuroleptics. Behavioral and neurochemical changes induced by methamphetamine treatment were studied as an animal model of schizophrenia, and both a decrease of D 2 receptor density and an increase of DA release were detected. The monoamine hypothesis for manic-depressive psychosis was advanced on the basis of the effect of reserpine, monoamine oxidase inhibitor and antidepressants. 3 H-clonidine binding sites were increased in platelet membranes of depressive patients, 3 H-imipramine binding sites were decreased. The GABA A receptor is the target site for the action of anxiolytics and antiepileptics such as benzodiazepines and barbiturates. Recent developments in molecular biology techniques have revealed the structure of receptor proteins, which are classified into two receptor families, the G-protein coupled type (D 2 ) and the ion-channel type (GABA A ). (J.P.N.)

  5. Possible Relevance of Receptor-Receptor Interactions between Viral- and Host-Coded Receptors for Viral-Induced Disease

    Directory of Open Access Journals (Sweden)

    Luigi F. Agnati

    2007-01-01

    Full Text Available It has been demonstrated that some viruses, such as the cytomegalovirus, code for G-protein coupled receptors not only to elude the immune system, but also to redirect cellular signaling in the receptor networks of the host cells. In view of the existence of receptor-receptor interactions, the hypothesis is introduced that these viral-coded receptors not only operate as constitutively active monomers, but also can affect other receptor function by interacting with receptors of the host cell. Furthermore, it is suggested that viruses could also insert not single receptors (monomers, but clusters of receptors (receptor mosaics, altering the cell metabolism in a profound way. The prevention of viral receptor-induced changes in host receptor networks may give rise to novel antiviral drugs that counteract viral-induced disease.

  6. 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.

  7. Peptide Receptor Radionuclide Therapy & Oncology

    NARCIS (Netherlands)

    H. Bergsma (Hendrik)

    2017-01-01

    markdownabstractNeuroendocrine tumors (NETs) are rare neoplasms with differences in clinical presentation, course and prognosis. Most of the NETs express the somatostatine receptor, which can be utilized for imaging and therapy. Radiolabeled somatostatin analogs can be used for peptide receptor

  8. Hydrocarbon Receptor Pathway in Dogs

    NARCIS (Netherlands)

    Steenbeek, F.G. van; Spee, B.; Penning, L.C.; Kummeling, A.; Gils, I.H.M.; Grinwis, G.C.M.; Leenen, D. van; Holstege, F.C.P.; Vos-Loohuis, M.; Rothuizen, J.; Leegwater, P.A.J.

    The aryl hydrocarbon receptor (AHR) mediates biological responses to toxic chemicals. An unexpected role for AHR in vascularization was suggested when mice lacking AHR displayed impaired closure of the ductus venosus after birth, as did knockout mice for aryl hydrocarbon receptor interacting

  9. Coronavirus spike-receptor interactions

    NARCIS (Netherlands)

    Mou, H.

    2015-01-01

    Coronaviruses cause important diseases in humans and animals. Coronavirus infection starts with the virus binding with its spike proteins to molecules present on the surface of host cells that act as receptors. This spike-receptor interaction is highly specific and determines the virus’ cell, tissue

  10. Neurobeachin regulates neurotransmitter receptor trafficking to synapses

    NARCIS (Netherlands)

    Nair, R.; Lauks, J.; Jung, S; Cooke, N.E.; de Wit, H.; Brose, N.; Kilimann, M.W.; Verhage, M.; Rhee, J.

    2013-01-01

    The surface density of neurotransmitter receptors at synapses is a key determinant of synaptic efficacy. Synaptic receptor accumulation is regulated by the transport, postsynaptic anchoring, and turnover of receptors, involving multiple trafficking, sorting, motor, and scaffold proteins. We found

  11. Probing Biased Signaling in Chemokine Receptors

    DEFF Research Database (Denmark)

    Amarandi, Roxana Maria; Hjortø, Gertrud Malene; Rosenkilde, Mette Marie

    2016-01-01

    The chemokine system mediates leukocyte migration during homeostatic and inflammatory processes. Traditionally, it is described as redundant and promiscuous, with a single chemokine ligand binding to different receptors and a single receptor having several ligands. Signaling of chemokine receptor...

  12. Dopamine Receptors and Parkinson's Disease

    Directory of Open Access Journals (Sweden)

    Shin Hisahara

    2011-01-01

    Full Text Available Parkinson's disease (PD is a progressive extrapyramidal motor disorder. Pathologically, this disease is characterized by the selective dopaminergic (DAergic neuronal degeneration in the substantia nigra. Correcting the DA deficiency in PD with levodopa (L-dopa significantly attenuates the motor symptoms; however, its effectiveness often declines, and L-dopa-related adverse effects emerge after long-term treatment. Nowadays, DA receptor agonists are useful medication even regarded as first choice to delay the starting of L-dopa therapy. In advanced stage of PD, they are also used as adjunct therapy together with L-dopa. DA receptor agonists act by stimulation of presynaptic and postsynaptic DA receptors. Despite the usefulness, they could be causative drugs for valvulopathy and nonmotor complication such as DA dysregulation syndrome (DDS. In this paper, physiological characteristics of DA receptor familyare discussed. We also discuss the validity, benefits, and specific adverse effects of pharmaceutical DA receptor agonist.

  13. Ryanodine receptor channelopathies

    Science.gov (United States)

    Betzenhauser, Matthew J.

    2010-01-01

    Ryanodine receptors (RyR) are intracellular Ca2+-permeable channels that provide the sarcoplasmic reticulum Ca2+ release required for skeletal and cardiac muscle contractions. RyR1 underlies skeletal muscle contraction, and RyR2 fulfills this role in cardiac muscle. Over the past 20 years, numerous mutations in both RyR isoforms have been identified and linked to skeletal and cardiac diseases. Malignant hyperthermia, central core disease, and catecholaminergic polymorphic ventricular tachycardia have been genetically linked to mutations in either RyR1 or RyR2. Thus, RyR channelopathies are both of interest because they cause significant human diseases and provide model systems that can be studied to elucidate important structure–function relationships of these ion channels. PMID:20179962

  14. Molecular characterization of opioid receptors

    Energy Technology Data Exchange (ETDEWEB)

    Howard, A.D.

    1986-01-01

    The aim of this research was to purify and characterize active opioid receptors and elucidate molecular aspects of opioid receptor heterogeneity. Purification to apparent homogeneity of an opioid binding protein from bovine caudate was achieved by solubilization in the non-ionic detergent, digitonin, followed by sequential chromatography on the opiate affinity matrix, ..beta..-naltrexylethylenediamine-CH-Sepharose 4B, and on the lectine affinity matrix, wheat germ agglutinin-agarose. Polyacrylamide gel electrophoresis in the presence of sodium dodecyl sulfate (SDS-PAGE) followed by autoradiography revealed that radioiodinated purified receptor gave a single band. Purified receptor preparations showed a specific activity of 12,000-15,000 fmol of opiate bound per mg of protein. Radioiodinated human beta-endorphin (/sup 125/I-beta-end/sub H/) was used as a probe to investigate the ligand binding subunits of mu and delta opioid receptors. /sup 125/I-beta-end/sub H/ was shown to bind to a variety of opioid receptor-containing tissues with high affinity and specificity with preference for mu and delta sites, and with little, if any, binding to kappa sites. Affinity crosslinking techniques were employed to covalently link /sup 125/I-beta-end/sub H/ to opioid receptors, utilizing derivatives of bis-succinimidyl esters that are bifunctional crosslinkers with specificities for amino and sulfhydryl groups. This, and competition experiments with high type-selective ligands, permitted the assignment of two labeled peptides to their receptor types, namely a peptide of M/sub r/ = 65,000 for mu receptors and one of M/sub r/ = 53,000 for delta receptors.

  15. Long-term insulin-like growth factor-I expression in skeletal muscles attenuates the enhanced in vitro proliferation ability of the resident satellite cells in transgenic mice

    Science.gov (United States)

    Chakravarthy, M. V.; Fiorotto, M. L.; Schwartz, R. J.; Booth, F. W.

    2001-01-01

    Insulin-like growth factor-I (IGF-I) overexpression for 1-month in mouse skeletal muscle increases satellite cell proliferation potential. However, it is unknown whether this beneficial enhancement by IGF-I expression would persist over a longer-term duration in aged mice. This is an important issue to address if a prolonged course of IGF-I is to be used clinically in muscle-wasting conditions where satellite cells may become limiting. Using the IGF-I transgenic (IGF-I Tg) mouse that selectively expresses the IGF-I transgene in striated muscles, we found that 18-months of continuous IGF-I overexpression led to a loss in the enhanced in vitro proliferative capacity of satellite cells from Tg skeletal muscles. Also 18-month-old IGF-I Tg satellite cells lost the enhanced BrdU incorporation, greater pRb and Akt phosphorylations, and decreased p27(Kip1) levels initially observed in cells from 1-month-old IGF-I Tg mice. The levels of those biochemical markers reverted to similar values seen in the 18-months WT littermates. These findings, therefore, suggest that there is no further beneficial effect on enhancing satellite cell proliferation ability with persistent long-term expression of IGF-I in skeletal muscles of these transgenic mice.

  16. Cloning and expression analysis of myostatin, fibroblast growth factor 6, insulin-like growth factor I and II in liver and muscle of sea bass (Dicentrarchus labrax, L. during long-term fasting and refeeding

    Directory of Open Access Journals (Sweden)

    M. Saroglia

    2010-04-01

    Full Text Available The exceptionally fast growth that fish experience after periods of fasting has been called “compensatory growth”. This phenomenon has been studied in intensive aquaculture as a means of enhancing growth rates, but the mechanisms by which food intake activates an increase in somatic growth, and especially in muscle growth, are complex and not yet fully understood. In the present paper, we describe the molecular cloning and sequencing of sea bass (Dicentrarchus labrax myostatin (MSTN and fibroblast growth factor 6 (FGF6, which have been shown to be major genetic determinants of skeletal muscle growth, together with insulin-like growth factor I (IGFI and IGF-II, which are potent mitogens known to play important roles in growth and development. We then report the pattern of expression of the four aforementioned genes, in liver and myotomal muscle in response to prolonged fasting and refeeding. Nutritional status significantly influenced the expression of IGF-I, IGF-II and MSTN, whereas the muscular FGF6 expression levels were not affected by the feeding status of the animals. Taken together these data indicate that IGF-I, IGF-II and MSTN are involved in the sea bass muscle compensatory growth induced by refeeding, whereas FGF6 probably has not a role in this phenomenon.

  17. 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 some...... controversy still exists. In adults, the diagnostic value of IGF-I and IGFBP-3 suspected of GHD has been reported in only a few studies. We performed a GH provocative test, using oral clonidine, in 108 patients who had previously been treated with GH during childhood (73 men and 35 women). Basal IGF......-I and IGFBP-3 levels were compared to those in 1237 healthy controls (312 controls > 18 yr) as well as to peak GH levels. Seventy-nine patients had peak GH values below a cut-off value of 7.5 micrograms/L (34 with isolated GHD), whereas 29 patients had a normal GH response (28 with previous isolated GHD), i...

  18. Estrogen-related receptor β (ERRβ) - renaissance receptor or receptor renaissance?

    Science.gov (United States)

    Divekar, Shailaja D; Tiek, Deanna M; Fernandez, Aileen; Riggins, Rebecca B

    2016-01-01

    Estrogen-related receptors (ERRs) are founding members of the orphan nuclear receptor (ONR) subgroup of the nuclear receptor superfamily. Twenty-seven years of study have yet to identify cognate ligands for the ERRs, though they have firmly placed ERRα and ERRγ at the intersection of cellular metabolism and oncogenesis. The pace of discovery for novel functions of ERRβ, however, has until recently been somewhat slower than that of its family members. ERRβ has also been largely ignored in summaries and perspectives of the ONR literature. Here, we provide an overview of established and emerging knowledge of ERRβ in mouse, man, and other species, highlighting unique aspects of ERRβ biology that set it apart from the other two estrogen-related receptors, with a focus on the impact of alternative splicing on the structure and function of this receptor.

  19. Corticosteroids decrease glomerular angiotensin receptors

    Energy Technology Data Exchange (ETDEWEB)

    Douglas, J.G.

    1987-03-01

    Angiotensin II (ANG II) receptors of glomerular mesangial cells are regulated in vivo by changes in Na balance, effects that are presumed to be secondary to changes in circulating ANG II. However, since changes in ANG II were accompanied by parallel changes in plasma aldosterone in all models tested, it is possible that aldosterone may have also participated in the modulation of glomerular ANG II receptors. To test this hypothesis, short-term aldosterone infusions within the physiological range were employed to favor actions that would be mediated through a high-affinity mineralocorticoid receptor. The glucocorticoid, dexamethasone, was also tested to determine the mineralocorticoid specificity of the response. Two infusion rates were associated with a decrease in glomerular /sup 125/I ANG II receptor density of 33 and 45%, respectively. Serum potassium and urinary Na/K ratio were lower in the aldosterone group. Spironolactone abolished the effect of aldosterone consistent with an action mediated through a specific mineralocorticoid receptor. These studies support the hypothesis that corticosteroids modulate glomerular ANG II receptors and validate the complexity of glomerular receptor modulation. The downregulation observed would be expected to diminish the ability of ANG II to influence glomerular hemodynamics in models such as mineralocorticoid and glucocorticoid-induced hypertension.

  20. Radioiodinated ligands for dopamine receptors

    International Nuclear Information System (INIS)

    Kung, H.F.

    1994-01-01

    The dopamine receptor system is important for normal brain function; it is also the apparent action site for various neuroleptic drugs for the treatment of schizophrenia and other metal disorders. In the past few years radioiodinated ligands for single photon emission tomography (SPECT) have been successfully developed and tested in humans: [ 123 I]TISCH for D1 dopamine receptors; [ 123 I]IBZM, epidepride, IBF and FIDA2, four iodobenzamide derivatives, for D2/D3 dopamine receptors. In addition, [ 123 I]β-CIT (RTI-55) and IPT, cocaine derivatives, for the dopamine reuptake site are potentially useful for diagnosis of loss of dopamine neurons. The first iodinated ligand, (R)trans-7-OH-PIPAT, for D3 dopamine receptors, was synthesized and characterized with cloned cell lines (Spodoptera frugiperda, Sf9) expressing the D2 and D3 dopamine receptors and with rat basal forebrain membrane preparations. Most of the known iodobenzamides displayed similar potency in binding to both D2 and D3 dopamine receptors expressed in the cell lines. Initial studies appear to suggest that by fine tuning the structures it may be possible to develop agents specific for D2 and D3 dopamine receptors. It is important to investigate D2/D3 selectivity for this series of potent ligands

  1. Lysophospholipid receptors in drug discovery.

    Science.gov (United States)

    Kihara, Yasuyuki; Mizuno, Hirotaka; Chun, Jerold

    2015-05-01

    Lysophospholipids (LPs), including lysophosphatidic acid (LPA), sphingosine 1-phospate (S1P), lysophosphatidylinositol (LPI), and lysophosphatidylserine (LysoPS), are bioactive lipids that transduce signals through their specific cell-surface G protein-coupled receptors, LPA1-6, S1P1-5, LPI1, and LysoPS1-3, respectively. These LPs and their receptors have been implicated in both physiological and pathophysiological processes such as autoimmune diseases, neurodegenerative diseases, fibrosis, pain, cancer, inflammation, metabolic syndrome, bone formation, fertility, organismal development, and other effects on most organ systems. Advances in the LP receptor field have enabled the development of novel small molecules targeting LP receptors for several diseases. Most notably, fingolimod (FTY720, Gilenya, Novartis), an S1P receptor modulator, became the first FDA-approved medicine as an orally bioavailable drug for treating relapsing forms of multiple sclerosis. This success is currently being followed by multiple, mechanistically related compounds targeting S1P receptor subtypes, which are in various stages of clinical development. In addition, an LPA1 antagonist, BMS-986020 (Bristol-Myers Squibb), is in Phase 2 clinical development for treating idiopathic pulmonary fibrosis, as a distinct compound, SAR100842 (Sanofi) for the treatment of systemic sclerosis and related fibrotic diseases. This review summarizes the current state of drug discovery in the LP receptor field. Copyright © 2014 Elsevier Inc. All rights reserved.

  2. A transient receptor potential channel expressed in taste receptor cells.

    Science.gov (United States)

    Pérez, Cristian A; Huang, Liquan; Rong, Minqing; Kozak, J Ashot; Preuss, Axel K; Zhang, Hailin; Max, Marianna; Margolskee, Robert F

    2002-11-01

    We used differential screening of cDNAs from individual taste receptor cells to identify candidate taste transduction elements in mice. Among the differentially expressed clones, one encoded Trpm5, a member of the mammalian family of transient receptor potential (TRP) channels. We found Trpm5 to be expressed in a restricted manner, with particularly high levels in taste tissue. In taste cells, Trpm5 was coexpressed with taste-signaling molecules such as alpha-gustducin, Ggamma13, phospholipase C-beta2 (PLC-beta2) and inositol 1,4,5-trisphosphate receptor type III (IP3R3). Our heterologous expression studies of Trpm5 indicate that it functions as a cationic channel that is gated when internal calcium stores are depleted. Trpm5 may be responsible for capacitative calcium entry in taste receptor cells that respond to bitter and/or sweet compounds.

  3. Receptors for and effects of insulin and IGF-I in rat glomerular mesangial cells

    International Nuclear Information System (INIS)

    Arnqvist, H.J.; Ballermann, B.J.; King, G.L.

    1988-01-01

    Receptors for and biological effects of insulin and insulin-like growth factor I (IGF-I) were studied in cultured rat renal mesangial cells. Specific binding of 125 I-IGF was over 200-fold greater than the specific binding of 125 I-insulin. Fifty percent inhibition of 126 I-insulin binding was obtained with 8 x 10 -9 M unlabeled insulin. For 125 I-IGF-I, 50% inhibition required 1.8 x 10 -9 M unlabeled IGF-I. 125 I-IGF-I was also displaced by IGF-II and insulin but at 10- and 100-fold lower potencies, respectively, than IGF-I. Cross-linking of 125 I-insulin and 125 I-IGF-I to their receptors, using disuccinimidyl suberate (DSS), and identification of the receptor with sodium dodecyl sulfate-polyacrylamide gel electrophoresis and autoradiography showed a band with a molecular mass of 135 kDa, probably corresponding to the α-subunit of the insulin receptor and a major band with a molecular mass of 145 kDa for the α-subunit of the IGF-I receptor. Both insulin and IGF-I stimulated the incorporation of [ 3 H]thymidine into DNA. A half-maximal effect was obtained at 1.6 x 10 -8 M for insulin and 1.2 x 10 -9 M for IGF-I. No additive effect on DNA synthesis was observed. Insulin at 8 x 10 -10 M increased the accumulation of [ 14 C]glucose in mesangial cells, whereas IGF-I was 10-fold less potent

  4. Parathyroid hormone receptor signalling in osterix-expressing mesenchymal progenitors is essential for tooth root formation

    Science.gov (United States)

    Ono, Wanida; Sakagami, Naoko; Nishimori, Shigeki; Ono, Noriaki; Kronenberg, Henry M.

    2016-01-01

    Dental root formation is a dynamic process in which mesenchymal cells migrate toward the site of the future root, differentiate and secrete dentin and cementum. However, the identities of dental mesenchymal progenitors are largely unknown. Here we show that cells expressing osterix are mesenchymal progenitors contributing to all relevant cell types during morphogenesis. The majority of cells expressing parathyroid hormone-related peptide (PTHrP) are in the dental follicle and on the root surface, and deletion of its receptor (PPR) in these progenitors leads to failure of eruption and significantly truncated roots lacking periodontal ligaments. The PPR-deficient progenitors exhibit accelerated cementoblast differentiation with upregulation of nuclear factor I/C (Nfic). Deletion of histone deacetylase-4 (HDAC4) partially recapitulates the PPR deletion root phenotype. These findings indicate that PPR signalling in dental mesenchymal progenitors is essential for tooth root formation, underscoring importance of the PTHrP–PPR system during root morphogenesis and tooth eruption. PMID:27068606

  5. Quantitative receptor radioautography in the study of receptor-receptor interactions in the nucleus tractus solitarii

    Directory of Open Access Journals (Sweden)

    Fior-Chadi D.R.

    1998-01-01

    Full Text Available The nucleus tractus solitarii (NTS in the dorsomedial medulla comprises a wide range of neuropeptides and biogenic amines. Several of them are related to mechanisms of central blood pressure control. Angiotensin II (Ang II, neuropeptide Y (NPY and noradrenaline (NA are found in the NTS cells, as well as their receptors. Based on this observation we have evaluated the modulatory effect of these peptide receptors on a2-adrenoceptors in the NTS. Using quantitative receptor radioautography, we observed that NPY and Ang II receptors decreased the affinity of a2-adrenoceptors for their agonists in the NTS of the rat. Cardiovascular experiments agreed with the in vitro data. Coinjection of a threshold dose of Ang II or of the NPY agonists together with an ED50 dose of adrenergic agonists such as NA, adrenaline and clonidine counteracted the depressor effect produced by the a2-agonist in the NTS. The results provide evidence for the existence of an antagonistic interaction between Ang II at1 receptors and NPY receptor subtypes with the a2-adrenoceptors in the NTS. This receptor interaction may reduce the transduction over the a2-adrenoceptors which can be important in central cardiovascular regulation and in the development of hypertension

  6. Regulation of gonadotropin receptors, gonadotropin responsiveness, and cell multiplication by somatomedin-C and insulin in cultured pig Leydig cells

    International Nuclear Information System (INIS)

    Bernier, M.; Chatelain, P.; Mather, J.P.; Saez, J.M.

    1986-01-01

    The author have investigated the effects of insulin and somatomedin-C/insulin like growth factor I(Sm-C) in purified porcine Leydig cells in vitro on gonadotrophins (hCG) receptor number, hCG responsiveness (cAMP and testosterone production), and thymidine incorporation into DNA. Leydig cells cultured in a serum-free medium containing transferrin, vitamin E, and insulin (5 μg/ml) maintained fairly constant both hCG receptors and hCG responsiveness. When they were cultured for 3 days in the same medium without insulin, there was a dramatic decline (more than 80%) in both hCG receptor number and hCG responsiveness. However the cAMP but not the testosterone response to forskolin was normal. Both insulin and Sm-C at nanomolar concentrations prevent the decline of both hCG receptors and hCG-induced cAMP production. At nanomolar concentrations, Sm-C and insulin enhanced hCG-induced testosterone production but the effect of Sm-C was significantly higher than that of insulin. However, the effect of insulin at higher concentrations (5 μg/ml) was significantly higher than that of Sm-C at 50 ng/ml. In contrast, at nanomolar concentrations only Sm-C stimulated [ 3 H]-thymidine incorporation into DNA and cell multiplication, the stimulatory effect of insulin on these parameters, was seen only at micromolar concentrations. These results indicate that both Sm-C and insulin acting through the receptors increase Leydig cell steroidogenic responsiveness to hCG by increasing hCG receptor number and improving some step beyond cAMP formation. In contrast, the mitogenic effects of insulin are mediated only through Sm-C receptors

  7. Glutamate receptor ligands

    DEFF Research Database (Denmark)

    Guldbrandt, Mette; Johansen, Tommy N; Frydenvang, Karla Andrea

    2002-01-01

    Homologation and substitution on the carbon backbone of (S)-glutamic acid [(S)-Glu, 1], as well as absolute stereochemistry, are structural parameters of key importance for the pharmacological profile of (S)-Glu receptor ligands. We describe a series of methyl-substituted 2-aminoadipic acid (AA...... or slightly lower potencies than (S)-AA [e.g., EC(50) = 76 microM for (2S,4S)-4-methyl-AA (5a) as compared to EC(50) = 35 microM for (S)-AA]. The position of the methyl substituent had a profound effect on the observed pharmacology, whereas the absolute stereochemistry at the methylated carbon atom had a very......) analogs, and the synthesis, stereochemistry, and enantiopharmacology of 3-methyl-AA (4a-d), 4-methyl-AA (5a-d), 5-methyl-AA (6a-d), and (E)-Delta(4)-5-methyl-AA (7a and 7b) are reported. The compounds were resolved using chiral HPLC and the configurational assignments of the enantiomers were based on X...

  8. Nuclear Receptor Signaling Atlas (NURSA)

    Data.gov (United States)

    U.S. Department of Health & Human Services — The Nuclear Receptor Signaling Atlas (NURSA) is designed to foster the development of a comprehensive understanding of the structure, function, and role in disease...

  9. L-glutamate Receptor In Paramecium

    Science.gov (United States)

    Bernal-Martínez, Juan; Ortega-Soto, Arturo

    2004-09-01

    Behavioral, electrophysiological and biochemical experiments were performed in order to establish the presence of a glutamate receptor in the ciliate Paramecium. It was found that an AMPA/KA receptor is functionally expressed in Paramecium and that this receptor is immunologically and fillogenetically related to the AMPA/KA receptor present in vertebrates.

  10. Receptor-targeted metalloradiopharmaceuticals. Final technical report

    International Nuclear Information System (INIS)

    Green, Mark A.

    2000-01-01

    Copper (II) and platinum (II) coordination complexes were prepared and characterized. These complexes were designed to afford structural homology with steroidal and non-steroidal estrogens for possible use as receptor-targeted radiopharmaceuticals. While weak affinity for the estrogen receptor was detectable, none would appear to have sufficient receptor-affinity for estrogen-receptor-targeted imaging or therapy

  11. [The receptor theory of atherosclerosis].

    Science.gov (United States)

    Likhoded, V G; Bondarenko, V M; Gintsburg, A L

    2010-01-01

    Lipopolysaccharides of Gram-negative bacteria can interact with Toll-like receptor 4 (TLR4) and induce atheroma formation. The risk of atherosclerosis is decreased in case of TLR4 mutation. Other bacterial ligands and endogenous ligands of TLRs can also be involved in induction of atherogenesis. The general concept of atherosclerosis pathogentsis is presented. According to this concept atherogenesis can be initiated by some reactions resulting from interaction of exogenous and endogenous microbial ligands with Toll-like receptors.

  12. Short-term effects of replacing milk with cola beverages on insulin-like growth factor-I and insulin-glucose metabolism: a 10 d interventional study in young men.

    Science.gov (United States)

    Hoppe, Camilla; Kristensen, Mette; Boiesen, Marlene; Kudsk, Jane; Fleischer Michaelsen, Kim; Mølgaard, Christian

    2009-10-01

    In the Western world, a trend towards increased consumption of carbonated soft drinks combined with a decreasing intake of milk is observed. This may affect circulating insulin-like growth factor I (IGF-I) and fasting insulin, as seen in pre-pubertal children. The present study was designed to reflect the trend of replacing milk with carbonated beverages in young men and to study the effects of this replacement on IGF-I, IGF-binding protein 3 (IGFBP-3), IGF-I:IGFBP-3 and glucose-insulin metabolism. A randomised, controlled crossover intervention study, in which eleven men aged 22-29 years were given a low-Ca diet in two 10 d periods with 10 d washout in between. In one period, they drank 2.5 litres of Coca Cola(R) per day and the other period 2.5 litres of semi-skimmed milk. Serum IGF-I, IGFBP-3 (RIA), insulin (fluoro immunoassay) and glucose (Cobas) were determined at baseline and end point of each intervention period. Insulin resistance and beta-cell function were calculated with the homeostasis model assessment. A decrease in serum IGF-I was observed in the cola period compared with the milk period (P cola over a 10 d period decreases total IGF-I compared with a high intake of milk, with no effect on glucose-insulin metabolism in adult men. It is unknown whether this is a transient phenomenon or whether it has long-term consequences.

  13. Nonparallel changes of growth hormone (GH) and insulin-like growth factor-I, insulin-like growth factor binding protein-3, and GH-binding protein, after craniospinal irradiation and chemotherapy

    International Nuclear Information System (INIS)

    Nivot, S.; Adan, L.; Souberbielle, J.; Rappaport, R.; Brauner, R.; Benelli, C.; Clot, J.P.; Saucet, C.; Zucker, J.M.

    1994-01-01

    The authors studied the GH-insulin-like growth factor-I (IGF-I) axis serially over 24-36 months in six patients with medulloblastoma who underwent surgical removal of the tumor followed by craniospinal irradiation therapy for 6 weeks and then chemotherapy for 42 weeks. Eighteen and 24 months after beginning irradiation there was a decline in the peak GH secretory response to acute stimulation with arginine/insulin hypoglycemia. Six months after irradiation and during chemotherapy there was a transient decline in IGF-I, IGF binding protein-3 (IGFBP-3), and GH-BP values (respective mean values of 56.1 ± 9.0 ng/mL, 1.1 ± 0.2 μg/mL, and 7.6 ± 3.3% of radioactivity as compared to time 0 values: 139 ± 15 ng/mL, 2.2 ± 0.2 μg/mL, and 20.0 ± 4.0%, P < 0.001), although provoked GH secretion was normal at this time. The IGF-I, IGFBP-3, and GH-BP returned to pretreatment ranges by 12-36 months after initiation of the study. There was also a decline in body mass index and serum protein values at 6 months after irradiation in ligand and immunoblot analysis there was a decline in IGFBP-3 and an abnormal electrophoretic mobility of IGFBP-2 that were both normalized at 36 months. In one patient they observed a high level of IGFBP-3 proteolysis at this time. This study demonstrates that before the decrease of GH secretion in patients receiving cranial irradiation there is a transient phase of GH insensitivity that may be characteristic of the acute therapeutic phase including the chemotherapy. This partial insensitivity may explain the early growth retardation observed in these patients. 28 refs., 4 figs., 1 tab

  14. Production and characterization of recombinantly derived peptides and antibodies for accurate determinations of somatolactin, growth hormone and insulin-like growth factor-I in European sea bass (Dicentrarchus labrax).

    Science.gov (United States)

    de Celis, S Vega-Rubín; Gómez-Requeni, P; Pérez-Sánchez, J

    2004-12-01

    A specific radioimmunoassay (RIA) for European sea bass (Dicentrarchus labrax) growth hormone (GH) was developed and validated. For this purpose, a stable source of GH was produced by means of recombinant DNA technology in a bacteria system. The identity of the purified protein (ion exchange chromatography) was demonstrated by Western blot and a specific GH antiserum was raised in rabbit. In Western blot and RIA system, this antiserum recognized specifically native and recombinant GH, and it did not cross-react with fish prolactin (PRL) and somatolactin (SL). In a similar way, a specific polyclonal antiserum against the now available recombinant European sea bass SL was raised and used in the RIA system to a sensitivity of 0.3 ng/ml (90% of binding of tracer). Further, European sea bass insulin-like growth factor-I (IGF-I) was cloned and sequenced, and its high degree of identity with IGF-I peptides of barramundi, tuna, and sparid fish allowed the use of a commercial IGF-I RIA based on barramundi IGF-I antiserum. These assay tools assisted for the first time accurate determinations of SL and GH-IGF-I axis activity in a fish species of the Moronidae family. Data values were compared to those found with gilthead sea bream (Sparus aurata), which is currently used as a Mediterranean fish model for growth endocrinology studies. As a characteristic feature, the average concentration year round of circulating GH in growing mature males of European sea bass was higher than in gilthead sea bream. By contrast, the average concentration of circulating SL was lower. Concerning to circulating concentration of IGF-I, the measured plasma values for a given growth rate were also lower in European sea bass. These findings are discussed on the basis of a different energy status that might allowed a reduced but more continuous growth in European sea bass.

  15. 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

    Directory of Open Access Journals (Sweden)

    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.

  16. Odorant Receptor Desensitization in Insects

    Directory of Open Access Journals (Sweden)

    Hao Guo

    2017-12-01

    Full Text Available Insects and other arthropods transmit devastating human diseases, and these vectors use chemical senses to target humans. Understanding how these animals detect, respond, and adapt to volatile odorants may lead to novel ways to disrupt host localization or mate recognition in these pests. The past decade has led to remarkable progress in understanding odorant detection in arthropods. Insects use odorant-gated ion channels, first discovered in Drosophila melanogaster , to detect volatile chemicals. In flies, 60 “tuning” receptor subunits combine with a common subunit, Orco ( o dorant r eceptor co receptor to form ligand-gated ion channels. The mechanisms underlying odorant receptor desensitization in insects are largely unknown. Recent work reveals that dephosphorylation of serine 289 on the shared Orco subunit is responsible for slow, odor-induced receptor desensitization. Dephosphorylation has no effect on the localization of the receptor protein, and activation of the olfactory neurons in the absence of odor is sufficient to induce dephosphorylation and desensitization. These findings reveal a major component of receptor modulation in this important group of disease vectors, and implicate a second messenger feedback mechanism in this process.

  17. Nuclear Receptors, RXR, and the Big Bang.

    Science.gov (United States)

    Evans, Ronald M; Mangelsdorf, David J

    2014-03-27

    Isolation of genes encoding the receptors for steroids, retinoids, vitamin D, and thyroid hormone and their structural and functional analysis revealed an evolutionarily conserved template for nuclear hormone receptors. This discovery sparked identification of numerous genes encoding related proteins, termed orphan receptors. Characterization of these orphan receptors and, in particular, of the retinoid X receptor (RXR) positioned nuclear receptors at the epicenter of the "Big Bang" of molecular endocrinology. This Review provides a personal perspective on nuclear receptors and explores their integrated and coordinated signaling networks that are essential for multicellular life, highlighting the RXR heterodimer and its associated ligands and transcriptional mechanism. Copyright © 2014 Elsevier Inc. All rights reserved.

  18. Expression of GABAergic receptors in mouse taste receptor cells.

    Directory of Open Access Journals (Sweden)

    Margaret R Starostik

    Full Text Available BACKGROUND: Multiple excitatory neurotransmitters have been identified in the mammalian taste transduction, with few studies focused on inhibitory neurotransmitters. Since the synthetic enzyme glutamate decarboxylase (GAD for gamma-aminobutyric acid (GABA is expressed in a subset of mouse taste cells, we hypothesized that other components of the GABA signaling pathway are likely expressed in this system. GABA signaling is initiated by the activation of either ionotropic receptors (GABA(A and GABA(C or metabotropic receptors (GABA(B while it is terminated by the re-uptake of GABA through transporters (GATs. METHODOLOGY/PRINCIPAL FINDINGS: Using reverse transcriptase-PCR (RT-PCR analysis, we investigated the expression of different GABA signaling molecules in the mouse taste system. Taste receptor cells (TRCs in the circumvallate papillae express multiple subunits of the GABA(A and GABA(B receptors as well as multiple GATs. Immunocytochemical analyses examined the distribution of the GABA machinery in the circumvallate papillae. Both GABA(A-and GABA(B- immunoreactivity were detected in the peripheral taste receptor cells. We also used transgenic mice that express green fluorescent protein (GFP in either the Type II taste cells, which can respond to bitter, sweet or umami taste stimuli, or in the Type III GAD67 expressing taste cells. Thus, we were able to identify that GABAergic receptors are expressed in some Type II and Type III taste cells. Mouse GAT4 labeling was concentrated in the cells surrounding the taste buds with a few positively labeled TRCs at the margins of the taste buds. CONCLUSIONS/SIGNIFICANCE: The presence of GABAergic receptors localized on Type II and Type III taste cells suggests that GABA is likely modulating evoked taste responses in the mouse taste bud.

  19. Toll-like receptors in neonatal sepsis.

    LENUS (Irish Health Repository)

    O'Hare, Fiona M

    2013-06-01

    Toll-like receptors are vital transmembrane receptors that initiate the innate immune response to many micro-organisms. The discovery of these receptors has improved our understanding of host-pathogen interactions, and these receptors play an important role in the pathogenesis of multiple neonatal conditions such as sepsis and brain injury. Toll-like receptors, especially TLRs 2 and 4, are associated with necrotizing enterocolitis, periventricular leukomalacia and sepsis.

  20. NMDA receptor signaling: death or survival?

    OpenAIRE

    LUO, Tong; WU, Wei-Hua; CHEN, Bo-Shiun

    2011-01-01

    Glutamate-induced neuronal damage is mainly caused by overactivation of N-methyl-D-aspartate (NMDA) receptors. Conversely, normal physiological brain function and neuronal survival require adequate activation of NMDA receptors. Studies have revealed that NMDA receptor-induced neuronal death or survival is mediated through distinct subset of NMDA receptors triggering different intracellular signaling pathways. Here we discuss recent advances in the characterization of NMDA receptors in neurona...

  1. Regulation of NMDA Receptors by Phosphorylation

    OpenAIRE

    Chen, Bo-Shiun; Roche, Katherine W.

    2007-01-01

    N-methyl-D-aspartate (NMDA) receptors are critical for neuronal development and synaptic plasticity. The molecular mechanisms underlying the synaptic localization and functional regulation of NMDA receptors have been the subject of extensive studies. In particular, phosphorylation has emerged as a fundamental mechanism that regulates NMDA receptor trafficking and can alter the channel properties of NMDA receptors. Here we summarize recent advances in the characterization of NMDA receptor phos...

  2. Growth hormone-insulin-like growth factor-I axis in adult insulin-dependent diabetic patients: evidence for central hypersensitivity to growth hormone-releasing hormone and peripheral resistance to growth hormone.

    Science.gov (United States)

    Fainstein Day, P; Fagin, J A; Vaglio, R M; Litwak, L E; Picasso, M F; Gutman, R A

    1998-12-01

    The aim of this study was to assess the GH-IGFI axis, GH receptor availability, as reflected by the levels of GH-BP, and the amount of GH-dependent IGFBP-3 in adult IDDM patients with different degrees of metabolic control. Thus, 10 adult well-controlled IDDMs (HbA1 7.8 +/- 0.4%), 10 adult non-ketotic poorly controlled IDDMs (HbA1 13.3 +/- 7%) and 14 sex- and age-matched healthy controls were subjected to two intravenous GH-RH stimulation tests with 0.1 and 1.0 microg/kg body weight respectively, and a plasma IGF-1 generation test induced by the administration of hGH. Poorly controlled IDDM patients exhibited an exaggerated GH response to 1.0 microg/kg of GH-RH when compared to healthy control subjects. Low fasting plasma IGF-1 levels and a blunted IGF-1 response to exogenously administered hGH were also found in poorly controlled IDDMs when compared to the healthy control group. GH-BP levels were significantly lower in IDDMs than in normal controls, and correlated positively with the IGF-1 generation capacity after hGH. Serum IGFBP-3 levels measured by RIA were similar in IDDM and control groups. Good glycemic control for 5.7 +/- 0.9 months did not correct the above mentioned abnormalities of the GH-IGF-1 axis. Our findings suggest that IDDM is associated with a diminished availability of GH receptors and synthesis of IGF-1. GH might then increase as a compensatory mechanism, further down-regulating liver GH receptors, and thus perpetuating the initial abnormality.

  3. Studies on insulin receptor, 2

    International Nuclear Information System (INIS)

    Sakai, Yukio

    1979-01-01

    The present study is to investigate an influence of starvation and high fat diet on insulin receptor of the plasma membrane by means of radioreceptor assay using 125 I-labelled insulin. Male guinea pigs of Hartley strain were employed for the starvation study, and 125 I-insulin binding capacity on the plasma membrane of the liver and kidney was determined at 24, 48 and 72 hours of the fast after the last meal. Male rats of Wistar strain were employed for the high fat study where the diet containing 35% of butter was fed ad libitum for 38 or 68 days. The animals were killed at the fast of 12 hours, and 125 I-insulin binding capacity on the plasma membrane of the liver was determined. The results obtained are summarized as follows: 1) An increase in 125 I-insulin binding capacity on the plasma membrane of the liver and kidney was observed by the starvation for 24 to 72 hours. 2) The mechanism of the increase by starvation was considered to be different by the organs; it was due to an increase in number of insulin receptor in the liver, and due to an increase in affinity of insulin receptor in the kidney. 3) In non-obese rats fed with high fat diet, the number of insulin receptor on the liver plasma membrane showed a decrease, and this observation clearly indicated that the decrease in number of the receptor did not depend on the obesity. 4) Obese rats also fed with high fat diet presented a decrease in number of insulin receptor without an elevation of insulin levels in the circulating blood. This indicated that at least in the obese rats fed with high fat diet, the decrease in number of the receptor was not due to hyperinsulinemia. (author)

  4. Purinergic Receptors in Ocular Inflammation

    Directory of Open Access Journals (Sweden)

    Ana Guzman-Aranguez

    2014-01-01

    Full Text Available Inflammation is a complex process that implies the interaction between cells and molecular mediators, which, when not properly “tuned,” can lead to disease. When inflammation affects the eye, it can produce severe disorders affecting the superficial and internal parts of the visual organ. The nucleoside adenosine and nucleotides including adenine mononucleotides like ADP and ATP and dinucleotides such as P1,P4-diadenosine tetraphosphate (Ap4A, and P1,P5-diadenosine pentaphosphate (Ap5A are present in different ocular locations and therefore they may contribute/modulate inflammatory processes. Adenosine receptors, in particular A2A adenosine receptors, present anti-inflammatory action in acute and chronic retinal inflammation. Regarding the A3 receptor, selective agonists like N6-(3-iodobenzyl-5′-N-methylcarboxamidoadenosine (CF101 have been used for the treatment of inflammatory ophthalmic diseases such as dry eye and uveoretinitis. Sideways, diverse stimuli (sensory stimulation, large intraocular pressure increases can produce a release of ATP from ocular sensory innervation or after injury to ocular tissues. Then, ATP will activate purinergic P2 receptors present in sensory nerve endings, the iris, the ciliary body, or other tissues surrounding the anterior chamber of the eye to produce uveitis/endophthalmitis. In summary, adenosine and nucleotides can activate receptors in ocular structures susceptible to suffer from inflammatory processes. This involvement suggests the possible use of purinergic agonists and antagonists as therapeutic targets for ocular inflammation.

  5. 17beta-estradiol regulation of human growth hormone (hGH), insulin-like growth factor-I (IGF-I) and insulin-like growth factor binding protein-3 (IGFBP-3) axis in hypoestrogenic, hypergonadotropic women.

    Science.gov (United States)

    Milewicz, Tomasz; Krzysiek, Józef; Sztefko, Krystyna; Radowicki, Stanisław; Krzyczkowska-Sendrakowska, Magdalena

    2005-01-01

    Ovarian hormonal function may be as important contributing factor to hGH-IGF-I-IGFBP-3 axis as age. To examine plasma hGH, IGF-1 and IGFBP-3 levels in women with premature ovarian failure compared to healthy normal controls and postmenopausal ones. Group A-15 women with premature ovarian failure (POF) (mean: age 38.9+/-5.2 years, FSH 101.4+/-29.0 IU/l; 17beta-estradiol 22.5+/-14.6 ng/l). Group B consisted of 15 menopausal women (mean: age 54.7+/-2.7 years; FSH 81.9+/-32.1 IU/l; 17beta-estradiol 17.1+/- 8.0 ng/l). Group C - controls - 15 normally menstruating women (mean: age 37.1+/-9.0 years; FSH 6.2+/-1.0 IU/l; 17beta-estradiol 144.8+/-117.1 ng/l). Body mass and BMI were measured. Basic fasting plasma hGH, IGF-I, IGFBP-3, insulin, testosterone and LH as well as prolactin (PRL), FSH and estradiol were assessed by RIA kits. Statistical analysis. Shapiro-Wilk test, Mann-Whitney u-test, Spearman rang correlation coefficient, stepwise multiple regression. Mean serum IGF-I level was the lowest (phGH levels. Women in group A and C were younger (phGH levels in group C (r=-0.54; phGH/IGF-1 as well as IGFBP-3/hGH relations were found. Prolactin accounted for 69% of the variance in IGF-I level in the group B (p=0.003) and for 24% in group A (NS). Testosterone accounted for 88% (p=0.004) of the variance in IGF-I level in group B and IGFBP-3 was responsible for 86% (p=0.038) of the variance in IGF-I level in group C. Again IGFBP-3 was responsible for 47% (p=0.023) in group A and for 49% (p=0.04) in group B of the hGH variance. 17b-estradiol may be as important contributor to insulin-like growth factor-I (IGF-I) plasma level as age in hypoestrogenic, hypogonadotropic women.

  6. Photo-antagonism of the GABAA receptor.

    Science.gov (United States)

    Mortensen, Martin; Iqbal, Favaad; Pandurangan, Arun P; Hannan, Saad; Huckvale, Rosemary; Topf, Maya; Baker, James R; Smart, Trevor G

    2014-07-29

    Neurotransmitter receptor trafficking is fundamentally important for synaptic transmission and neural network activity. GABAA receptors and inhibitory synapses are vital components of brain function, yet much of our knowledge regarding receptor mobility and function at inhibitory synapses is derived indirectly from using recombinant receptors, antibody-tagged native receptors and pharmacological treatments. Here we describe the use of a set of research tools that can irreversibly bind to and affect the function of recombinant and neuronal GABAA receptors following ultraviolet photoactivation. These compounds are based on the competitive antagonist gabazine and incorporate a variety of photoactive groups. By using site-directed mutagenesis and ligand-docking studies, they reveal new areas of the GABA binding site at the interface between receptor β and α subunits. These compounds enable the selected inactivation of native GABAA receptor populations providing new insight into the function of inhibitory synapses and extrasynaptic receptors in controlling neuronal excitation.

  7. Scavenger receptors in homeostasis and immunity.

    Science.gov (United States)

    Canton, Johnathan; Neculai, Dante; Grinstein, Sergio

    2013-09-01

    Scavenger receptors were originally identified by their ability to recognize and to remove modified lipoproteins; however, it is now appreciated that they carry out a striking range of functions, including pathogen clearance, lipid transport, the transport of cargo within the cell and even functioning as taste receptors. The large repertoire of ligands recognized by scavenger receptors and their broad range of functions are not only due to the wide range of receptors that constitute this family but also to their ability to partner with various co-receptors. The ability of individual scavenger receptors to associate with different co-receptors makes their responsiveness extremely versatile. This Review highlights recent insights into the structural features that determine the function of scavenger receptors and the emerging role that these receptors have in immune responses, notably in macrophage polarization and in the pathogenesis of diseases such as atherosclerosis and Alzheimer's disease.

  8. Identification and mechanism of ABA receptor antagonism

    Energy Technology Data Exchange (ETDEWEB)

    Melcher, Karsten; Xu, Yong; Ng, Ley-Moy; Zhou, X. Edward; Soon, Fen-Fen; Chinnusamy, Viswanathan; Suino-Powell, Kelly M; Kovach, Amanda; Tham, Fook S.; Cutler, Sean R.; Li, Jun; Yong, Eu-Leong; Zhu, Jian-Kang; Xu, H. Eric (NU Sinapore); (Van Andel); (UCR)

    2010-11-11

    The phytohormone abscisic acid (ABA) functions through a family of fourteen PYR/PYL receptors, which were identified by resistance to pyrabactin, a synthetic inhibitor of seed germination. ABA activates these receptors to inhibit type 2C protein phosphatases, such as ABI1, yet it remains unclear whether these receptors can be antagonized. Here we demonstrate that pyrabactin is an agonist of PYR1 and PYL1 but is unexpectedly an antagonist of PYL2. Crystal structures of the PYL2-pyrabactin and PYL1-pyrabactin-ABI1 complexes reveal the mechanism responsible for receptor-selective activation and inhibition, which enables us to design mutations that convert PYL1 to a pyrabactin-inhibited receptor and PYL2 to a pyrabactin-activated receptor and to identify new pyrabactin-based ABA receptor agonists. Together, our results establish a new concept of ABA receptor antagonism, illustrate its underlying mechanisms and provide a rational framework for discovering novel ABA receptor ligands.

  9. Modulation of Xenobiotic Receptors by Steroids

    Directory of Open Access Journals (Sweden)

    Delira Robbins

    2013-06-01

    Full Text Available Nuclear receptors (NRs are ligand-activated transcription factors that regulate the expression of their target genes. NRs play important roles in many human diseases, including metabolic diseases and cancer, and are therefore a key class of therapeutic targets. Steroids play important roles in regulating nuclear receptors; in addition to being ligands of steroid receptors, steroids (and their metabolites also regulate other NRs, such as the pregnane X receptor and constitutive androstane receptor (termed xenobiotic receptors, which participate in steroid metabolism. Xenobiotic receptors have promiscuous ligand-binding properties, and their structurally diverse ligands include steroids and their metabolites. Therefore, steroids, their metabolism and metabolites, xenobiotic receptors, steroid receptors, and the respective signaling pathways they regulate have functional interactions. This review discusses these functional interactions and their implications for activities mediated by steroid receptors and xenobiotic receptors, focusing on steroids that modulate pathways involving the pregnane X receptor and constitutive androstane receptor. The emphasis of the review is on structure-function studies of xenobiotic receptors bound to steroid ligands.

  10. 5-Hydroxytryptamine type 7 receptor neuroprotection against NMDA-induced excitotoxicity is PDGFβ receptor dependent.

    Science.gov (United States)

    Vasefi, Maryam S; Kruk, Jeff S; Heikkila, John J; Beazely, Michael A

    2013-04-01

    The serotonin (5-HT) type 7 receptor is expressed throughout the CNS including the hippocampus. Long-term (2-24 h) activation of 5-HT7 receptors regulates growth factor receptor expression, including the expression of platelet-derived growth factor (PDGF) β receptors. Direct activation of PDGFβ receptors in primary hippocampal and cortical neurons inhibits NMDA receptor activity and attenuates NMDA receptor-induced neurotoxicity. Our objective was to investigate whether the 5-HT7 receptor-induced increase in PDGFβ receptor expression would be similarly neuroprotective. We demonstrate that 5-HT7 receptor agonist treatment in primary hippocampal neurons also increases the expression of phospholipase C (PLC) γ, a downstream effector of PDGFβ receptors associated with the inhibition of NMDA receptor activity. To determine if the up-regulation of PDGFβ receptors is neuroprotective, primary hippocampal neurons were incubated with the 5-HT7 receptor agonist, LP 12, for 24 h. Indeed, LP 12 treatment prevented NMDA-induced neurotoxicity and this effect was dependent on PDGFβ receptor kinase activity. Treatment of primary neurons with LP 12 also differentially altered NMDA receptor subunit expression, reducing the expression of NR1 and NR2B, but not NR2A. These findings demonstrate the potential for providing growth factor receptor-dependent neuroprotective effects using small-molecule ligands of G protein-coupled receptors. © 2013 International Society for Neurochemistry.

  11. Prolactin receptors in uterine leiomyomas

    International Nuclear Information System (INIS)

    Baban, Rayah S.; Farid, Yahya Y.; Al-Zuheiri, Shatha T.

    2008-01-01

    Objective was to identify the location of prolactin receptors in patientswith uterine leiomyomas and their host myometrium as well as normalmyometrium. A case control study was conducted at the College of MedicineAl-Nahrain University, Baghdad, Iraq during the period from 2004-2006. Thesamples were collected at Obstetrics and Gynecological Departments of 4hospitals in Baghdad City (Al-Khadimiya Teaching Hospital, Al-Noor,Al-Kharch, and Al-Sadoon Hospital). Sections from large and small tumors(n=53) with their host myometriums and from normal myometriums (n=40) werestained immunohistochemically for prolactin receptors. Prolactin receptorswere positively seen in all cases examined including patient and comparisontissues, in the form of dark brown staining. Staining was heterogeneous andvaried in intensity from one case to another and sometimes from one are toanother in the same section. The increase in prolactin receptors in leiomyomais expected given that the underlying host myometrium abnormal. (author)

  12. Mechanism for the activation of glutamate receptors

    Science.gov (United States)

    Scientists at the NIH have used a technique called cryo-electron microscopy to determine a molecular mechanism for the activation and desensitization of ionotropic glutamate receptors, a prominent class of neurotransmitter receptors in the brain and spina

  13. Genetics Home Reference: leptin receptor deficiency

    Science.gov (United States)

    ... People with leptin receptor deficiency also have hypogonadotropic hypogonadism, which is a condition caused by reduced production ... weight gain associated with this disorder. Because hypogonadotropic hypogonadism occurs in leptin receptor deficiency , researchers suggest that ...

  14. Excitatory amino acid receptor antagonists

    DEFF Research Database (Denmark)

    Johansen, T N; Frydenvang, Karla Andrea; Ebert, B

    1997-01-01

    We have previously shown that (RS)-2-amino-2-(5-tert-butyl-3-hydroxyisoxazol-4-yl)acetic acid (ATAA) is an antagonist at N-methyl-D-aspartic acid (NMDA) and (RS)-2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid (AMPA) receptors. We have now resolved ATAA via diastereomeric salt formation...

  15. Pharmacological approach of the receptors

    International Nuclear Information System (INIS)

    Puech, A.J.

    1989-01-01

    This paper explains the three main goals for clinical positron emission tomography (PET) studies: detection of receptor abnormalities in groups of patients to propose therapeutic indication of new ligands; validation of current hypothesis of drug effect; rational clinical drug development specially for dose-finding studies. (H.W.)

  16. Are olfactory receptors really olfactive?

    DEFF Research Database (Denmark)

    Giorgi, Franco; Maggio, Roberto; Bruni, Luis Emilio

    2011-01-01

    Any living organism interacts with and responds specifically to environmental molecules by expressing specific olfactory receptors. This specificity will be first examined in causal terms with particular emphasis on the mechanisms controlling olfactory gene expression, cell-to-cell interactions a...

  17. Cannabinoid receptor localization in brain

    Energy Technology Data Exchange (ETDEWEB)

    Herkenham, M.; Lynn, A.B.; Little, M.D.; Johnson, M.R.; Melvin, L.S.; de Costa, B.R.; Rice, K.C. (National Institute of Mental Health, Bethesda, MD (USA))

    1990-03-01

    (3H)CP 55,940, a radiolabeled synthetic cannabinoid, which is 10-100 times more potent in vivo than delta 9-tetrahydrocannabinol, was used to characterize and localize a specific cannabinoid receptor in brain sections. The potencies of a series of natural and synthetic cannabinoids as competitors of (3H)CP 55,940 binding correlated closely with their relative potencies in several biological assays, suggesting that the receptor characterized in our in vitro assay is the same receptor that mediates behavioral and pharmacological effects of cannabinoids, including human subjective experience. Autoradiography of cannabinoid receptors in brain sections from several mammalian species, including human, reveals a unique and conserved distribution; binding is most dense in outflow nuclei of the basal ganglia--the substantia nigra pars reticulata and globus pallidus--and in the hippocampus and cerebellum. Generally high densities in forebrain and cerebellum implicate roles for cannabinoids in cognition and movement. Sparse densities in lower brainstem areas controlling cardiovascular and respiratory functions may explain why high doses of delta 9-tetrahydrocannabinol are not lethal.

  18. Ligand-guided receptor optimization.

    Science.gov (United States)

    Katritch, Vsevolod; Rueda, Manuel; Abagyan, Ruben

    2012-01-01

    Receptor models generated by homology or even obtained by crystallography often have their binding pockets suboptimal for ligand docking and virtual screening applications due to insufficient accuracy or induced fit bias. Knowledge of previously discovered receptor ligands provides key information that can be used for improving docking and screening performance of the receptor. Here, we present a comprehensive ligand-guided receptor optimization (LiBERO) algorithm that exploits ligand information for selecting the best performing protein models from an ensemble. The energetically feasible protein conformers are generated through normal mode analysis and Monte Carlo conformational sampling. The algorithm allows iteration of the conformer generation and selection steps until convergence of a specially developed fitness function which quantifies the conformer's ability to select known ligands from decoys in a small-scale virtual screening test. Because of the requirement for a large number of computationally intensive docking calculations, the automated algorithm has been implemented to use Linux clusters allowing easy parallel scaling. Here, we will discuss the setup of LiBERO calculations, selection of parameters, and a range of possible uses of the algorithm which has already proven itself in several practical applications to binding pocket optimization and prospective virtual ligand screening.

  19. Molecular imaging of estrogen receptors

    NARCIS (Netherlands)

    van Kruchten, Michel

    2015-01-01

    For patients with estrogen receptor (ER) positive breast cancer, endocrine therapy plays a major role in both the adjuvant and palliative setting. For adequate treatment decision-making it is crucial to obtain up-to-date information on the ER-status of the tumor(s), since ER-expression is the sole

  20. Stability of solubilized benzodiazepine receptors

    NARCIS (Netherlands)

    Janssen, M.J; Ensing, K; de Zeeuw, R.A

    1997-01-01

    According to the observations of other researchers, benzodiazepine receptors solubilized with sodium deoxycholate are unstable, but stability can be improved by exchanging deoxycholate for Triton X-100. In our experiments we conclude that the choice of detergent is not the restrictive factor for the

  1. Uncompetitive antagonism of AMPA receptors

    DEFF Research Database (Denmark)

    Andersen, Trine F; Tikhonov, Denis B; Bølcho, Ulrik

    2006-01-01

    Philanthotoxins are uncompetitive antagonists of Ca2+-permeable AMPA receptors presumed to bind to the pore-forming region, but a detailed molecular mechanism for this interaction is missing. Here a small library of novel philanthotoxins was designed and synthesized using a solid-phase strategy. ...

  2. New horizons for lipoprotein receptors

    DEFF Research Database (Denmark)

    Andersen, Olav M.; Dagil, Robert; Kragelund, Birthe Brandt

    2013-01-01

    , this dogma has transformed with the observation that β-propellers of some LRs actively engage in complex formation too. Based on an in-depth decomposition of current structures and sequences, we suggest that exploitation of the β-propellers as binding targets depends on receptor subgroups. In particular, we...

  3. Virally encoded 7TM receptors

    DEFF Research Database (Denmark)

    Rosenkilde, M M; Waldhoer, M; Lüttichau, H R

    2001-01-01

    expression of this single gene in certain lymphocyte cell lineages leads to the development of lesions which are remarkably similar to Kaposi's sarcoma, a human herpesvirus 8 associated disease. Thus, this and other virally encoded 7TM receptors appear to be attractive future drug targets....

  4. Repeated blockade of mineralocorticoid receptors, but not of glucocorticoid receptors impairs food rewarded spatial learning

    NARCIS (Netherlands)

    Douma, BRK; Korte, SM; Buwalda, B; la Fleur, SE; Bohus, B; Luiten, PGM

    Corticosteroids from the adrenal cortex influence a variety of behaviours including cognition, learning and memory. These hormones act via two intracellular receptors, the mineralo-corticoid receptor (MR) and the glucocorticoid receptor (GR). These two receptor types display a high concentration and

  5. Repeated blockade of mineralocorticoid receptors, but not of glucocorticoid receptors impairs food rewarded spatial learning

    NARCIS (Netherlands)

    Douma, B. R.; Korte, S. M.; Buwalda, B.; La Fleur, S. E.; Bohus, B.; Luiten, P. G.

    1998-01-01

    Corticosteroids from the adrenal cortex influence a variety of behaviours including cognition, learning and memory. These hormones act via two intracellular receptors, the mineralo-corticoid receptor (MR) and the glucocorticoid receptor (GR). These two receptor types display a high concentration and

  6. The substance P/NK-1 receptor system: NK-1 receptor antagonists ...

    Indian Academy of Sciences (India)

    The substance P (SP)/neurokinin (NK)-1 receptor system plays an important role in cancer. SP promotes the proliferation of tumour cells, angiogenesis and the migration of tumour cells. We review the involvement of SP, the NK-1 receptor and NK-1 receptor antagonists in cancer. Tumour cells overexpress NK-1 receptors, ...

  7. Insulin-like growth factor-1 receptor expression in oral squamous cell carcinoma

    Directory of Open Access Journals (Sweden)

    Devipriyaa B. Sundaram

    2011-12-01

    Full Text Available Objectives: The Insulin-like growth factor-I receptor (IGF-1R plays critical roles in cancer development, proliferation, motility and survival. IGF-1R over expression is frequently found in various tumours and is often associated with an aggressive phenotype. Hence, the aim of the present study was to examine the expression of IGF-1R in normal oral mucosa, fibroepithelial polyps, dysplastic oral mucosa and well-differentiated squamous cell carcinomas.Materials and methods: A 3-layered streptavidin peroxidase immunohistochemical method was used to detect the expression of IGF-1R in normal oral mucosa, fibroepithelial polyps, dysplastic oral mucosa and well-differentiated squamous cell carcinomas.Results: All squamous cell carcinomas (15 out of 15 patients showed intense immunoreactivity for IGF-1R. Moderate immunoreactivity was seen in dysplastic oral lesions (12 out of 12 lesions with positive staining in the prickle cell layer. The staining distribution in the benign lesions (14 out of 14 lesions was weaker and similar to that seen in normal oral mucosa (10 out of 10 samples when compared to squamous cell carcinomas and dysplastic lesions.Conclusions: Our results demonstrate increased IGF-1 receptor expression in oral squamous cell carcinomas which suggests that IGF-1 may have an important role in the development of oral cancer. J Clin Exp Invest 2011; 2 (4: 354-361

  8. Muscarinic receptors and drugs in cardiovascular medicine

    NARCIS (Netherlands)

    van Zwieten, P. A.; Doods, H. N.

    1995-01-01

    The parasympathetic system and its associated muscarinic receptors have been the subject of a renaissance of interest for the following two main reasons: (1) the association of endothelial muscarinic receptors and the nitric oxide (NO) pathway; (2) the discovery of several muscarinic receptor

  9. A new family of insect tyramine receptors

    DEFF Research Database (Denmark)

    Cazzamali, Giuseppe; Klærke, Dan Arne; Grimmelikhuijzen, Cornelis J P

    2005-01-01

    in the genomic databases from the malaria mosquito Anopheles gambiae and the honeybee Apis mellifera. These four tyramine or tyramine-like receptors constitute a new receptor family that is phylogenetically distinct from the previously identified insect octopamine/tyramine receptors. The Drosophila tyramine...

  10. Metabotropic glutamate receptors in glial cells

    NARCIS (Netherlands)

    D'Antoni, Simona; Berretta, Antonio; Bonaccorso, Carmela Maria; Bruno, Valeria; Aronica, Eleonora; Nicoletti, Ferdinando; Catania, Maria Vincenza

    2008-01-01

    Glutamate is the major excitatory neurotransmitter in the mammalian central nervous system (CNS) and exerts its actions via a number of ionotropic glutamate receptors/channels and metabotropic glutamate (mGlu) receptors. In addition to being expressed in neurons, glutamate receptors are expressed in

  11. Neurotransmitter Receptor Binding in Bovine Cerebral Microvessels

    Science.gov (United States)

    Peroutka, Stephen J.; Moskowitz, Michael A.; Reinhard, John F.; Synder, Solomon H.

    1980-05-01

    Purified preparations of microvessels from bovine cerebral cortex contain substantial levels of alpha-adrenergic, beta-adrenergic, and histamine 1 receptor binding sites but only negligible serotonin, muscarinic cholinergic, opiate, and benzodiazepine receptor binding. Norepinephrine and histamine may be endogenous regulators of the cerebral microcirculation at the observed receptors.

  12. Imaging of receptors in clinical neurosciences

    NARCIS (Netherlands)

    Korf, J

    This article deals with the question why should one determine receptors in the brain with positron and single photon emission tomography (PET and SPECT, respectively). Radiopharmaceuticals for a wide variety of receptors are available now. Receptors studies with PET and SPECT have thus far focused

  13. Modified Receptor Internalization upon Coexpression of 5-HT1B Receptor and 5-HT2B Receptors

    OpenAIRE

    Janoshazi , Agnes; Deraet , Maud; Callebert , Jacques; Setola , Vincent; Guenther , Silke; Saubamea , Bruno; Manivet , Philippe; Launay , Jean-Marie; Maroteaux , Luc

    2007-01-01

    International audience; Serotonin 5-HT(2B) receptors are often coexpressed with 5-HT(1B) receptors, and cross-talk between the two receptors has been reported in various cell types. However, many mechanistic details underlying 5-HT(1B) and 5-HT(2B) receptor cross-talk have not been elucidated. We hypothesized that 5-HT(2B) and 5-HT(1B) receptors each affect the others' signaling by modulating the others' trafficking. We thus examined the agonist stimulated internalization kinetics of fluoresc...

  14. Triheteromeric NMDA Receptors at Hippocampal Synapses

    Science.gov (United States)

    Tovar, Kenneth R.; McGinley, Matthew J.; Westbrook, Gary L.

    2013-01-01

    NMDA receptors are composed of two GluN1 (N1) and two GluN2 (N2) subunits. Constituent N2 subunits control the pharmacological and kinetic characteristics of the receptor. NMDA receptors in hippocampal or cortical neurons are often thought of as diheteromeric, i.e., containing only one type of N2 subunit. However, triheteromeric receptors with more than one type of N2 subunit also have been reported and the relative contribution of di- and triheteromeric NMDA receptors at synapses has been difficult to assess. Because wild-type hippocampal principal neurons express N1, N2A and N2B, we used cultured hippocampal principal neurons from N2A and N2B-knockout mice as templates for diheteromeric synaptic receptors. Summation of N1/N2B and N1/N2A excitatory postsynaptic currents could not account for the deactivation kinetics of wild-type excitatory postsynaptic currents (EPSCs) however. To make a quantitative estimate of NMDA receptor subtypes at wild-type synapses, we used the deactivation kinetics, as well as the effects of the competitive antagonist NVP-AAM077. Our results indicate that three types of NMDA receptors contribute to the wild-type EPSC, with at least two-thirds being triheteromeric receptors. Functional isolation of synaptic triheteromeric receptors revealed deactivation kinetics and pharmacology distinct from either diheteromeric receptor subtype. Because of differences in open probability, synaptic triheteromeric receptors outnumbered N1/N2A receptors by 5.8 to 1 and N1/N2B receptors by 3.2 to 1. Our results suggest that triheteromeric NMDA receptors must be either preferentially assembled or preferentially localized at synapses. PMID:23699525

  15. The insulin-like growth factor system in chronic kidney disease: Pathophysiology and therapeutic opportunities

    Directory of Open Access Journals (Sweden)

    Youngman Oh

    2012-03-01

    therapeutic potential for CKD. Further understanding of GH–IGF–IGFBP etiopathophysiology in CKD may lead to the development of therapeutic strategies for this devastating disease. It would hold promise to use of GH, somatostatin analogs, IGFs, IGF agonists, GHR and insulin-like growth factor-I receptor (IGF-IR antagonists, IGFBP displacer, and IGFBP antagonists as well as a combination treatment as therapeutic agents for CKD.

  16. The insulin-like growth factor system in chronic kidney disease: Pathophysiology and therapeutic opportunities.

    Science.gov (United States)

    Oh, Youngman

    2012-03-01

    CKD. Further understanding of GH-IGF-IGFBP etiopathophysiology in CKD may lead to the development of therapeutic strategies for this devastating disease. It would hold promise to use of GH, somatostatin analogs, IGFs, IGF agonists, GHR and insulin-like growth factor-I receptor (IGF-IR) antagonists, IGFBP displacer, and IGFBP antagonists as well as a combination treatment as therapeutic agents for CKD.

  17. Some theoretical aspects of hormone receptor determination

    International Nuclear Information System (INIS)

    Sluiter, W.J.

    1981-01-01

    Suitable antisera for determination of hormone receptors are not available for the majority of hormone receptors. Therefore, the determination of hormone receptors is mostly performed in terms of binding capacity for the appropriate hormone, using radioactive hormone labels. Some theoretical aspects of such a receptor determination are discussed including the length of incubation (total or unoccupied receptor concentration), single point or multiple point (Scatchard) analysis (regarding the influence of other specific binders), the correction procedure for non-specific binding and the influence of the circulating hormone level. (Auth.)

  18. Epiphyseal growth plate growth hormone receptor signaling is decreased in chronic kidney disease-related growth retardation.

    Science.gov (United States)

    Troib, Ariel; Landau, Daniel; Kachko, Leonid; Rabkin, Ralph; Segev, Yael

    2013-11-01

    Linear growth retardation in children with chronic kidney disease (CKD) has been ascribed to insensitivity to growth hormone. This resistance state has been attributed to impaired growth hormone signaling through the JAK2/STAT5 pathway in liver and skeletal muscle leading to reduced insulin-like growth factor-I (IGF-I). Here we determine whether systemic and growth plate alterations in growth hormone signaling contribute to CKD-induced linear growth retardation using partially nephrectomized and pair-fed control 20-day-old rats. Serum growth hormone did not change in rats with CKD, yet serum IGF-I levels were decreased and growth retarded. The tibial growth plate hypertrophic zone was wider and vascularization at the primary ossification center was reduced in CKD. This was associated with a decrease in growth plate vascular endothelial growth factor (VEGF) mRNA and immunostainable VEGF and IGF-I levels. Growth plate growth hormone receptor and STAT5 protein levels were unchanged, while JAK2 was reduced. Despite comparable growth hormone and growth hormone receptor levels in CKD and control rats, relative STAT5 phosphorylation was significantly depressed in CKD. Of note, the mRNA of SOCS2, an inhibitor of growth hormone signaling, was increased. Thus, linear growth impairment in CKD can in part be explained by impaired long bone growth plate growth hormone receptor signaling through the JAK2/STAT5 pathway, an abnormality that may be caused by an increase in SOCS2 expression.

  19. Chapter 8. Activation mechanisms of chemokine receptors

    DEFF Research Database (Denmark)

    Jensen, Pia C; Rosenkilde, Mette M

    2009-01-01

    Chemokine receptors belong to the large family of 7-transmembrane (7TM) G-protein-coupled receptors. These receptors are targeted and activated by a variety of different ligands, indicating that activation is a result of similar molecular mechanisms but not necessarily similar modes of ligand...... binding. Attempts to unravel the activation mechanism of 7TM receptors have led to the conclusion that activation involves movements of the transmembrane segments VI and VII in particular, as recently gathered in the Global Toggle Switch Model. However, to understand the activation mechanism completely......, more research has to be done in this field. Chemokine receptors are interesting tools in this matter. First, the chemokine system has a high degree of promiscuity that allows several chemokines to target one receptor in different ways, as well as a single chemokine ligand to target several receptors...

  20. DMPD: Signal transduction by the lipopolysaccharide receptor, Toll-like receptor-4. [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available 15379975 Signal transduction by the lipopolysaccharide receptor, Toll-like receptor... Signal transduction by the lipopolysaccharide receptor, Toll-like receptor-4. PubmedID 15379975 Title Signa...l transduction by the lipopolysaccharide receptor, Toll-like receptor-4. Authors

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

    Directory of Open Access Journals (Sweden)

    M. Conchillo

    2007-03-01

    mejoría del metabolismo energético por efecto del IGF-I. Se precisan ensayos clínicos adicionales para identificar la dosis adecuada de IGF-I, el tiempo y ritmo de administración y el subgrupo de pacientes cirróticos que obtendrán mayor beneficio de este tratamiento sustitutivo.Insulin-like growth factor I (IGF-I is a polypeptide hormone secreted by multiple tissues in response to growth hormone (GH. It is partly responsible for GH activity, and also has glucose-lowering and anabolizing effects. Ninety percent of circulating IGF-I originates in the liver and has autocrine, paracrine, and endocrine effects, the latter on multiple tissues. Liver cirrhosis results in a progressive decline of hepatic IGF-I output, and this factor may become undetectable in advanced disease. Some cirrhosis complications, mainly those nutritional and metabolic in nature (insuline resistance, malnutrition, osteopenia, hypogonadism, intestinal disorders, may be at least partly related to this IGF-I deficiency, since some IGF-I effects represent a reverse image of cirrhosis complications. Despite this, IGF-I replacement therapy has been never suggested for cirrhosis. A number of experimental studies in cirrhotic rats showed that therapy using low-dose recombinant IGF-I exerts two types of effect on experimental cirrhosis: a liver improvement driven by improved hepatocellular function, portal hypertension, and liver fibrosis; and b cirrhosis-related extrahepatic disorder improvement driven by improved food efficiency, muscle mass, bone mass, gonadal function and structure, and intestinal function and structure, with a normalization of sugar and amino acid malabsorption, and improved intstinal barrier function, manifested by reduced endotoxemia and bacterial translocation. Subsequently, the first randomized, double-blind, placebo-controlled, pilot clinical trial in a small number of cirrhotic patients showed increased serum albumin and improved energy metabolism as a result of IGF-I use

  2. Further characterization of tuftsin receptors

    Energy Technology Data Exchange (ETDEWEB)

    Bump, N.J.; Lee, J.; Najjar, V.A.

    1986-03-05

    Tuftsin receptor was purified from rabbit peritoneal granulocytes by affinity chromatography. The pentapeptide analog, Thr-Lys-Pro-Pro-Arg was covalently linked to a solid support column. Rabbit granulocyte membrane was prepared, dissolved in 8 mM CHAPS and run through the column, eluted with 20 eta M free pentapeptide and subjected to dialysis concentration. When this was run on SDS-PAGE, two bands were obtained at a migration equivalent to Mr 60 and 62 K. These were electroblotted on nitrocellulose paper which showed two corresponding (/sup 3/H)-tuftsin binding bands. After reduction, and boiling, SDS-PAGE runs showed two bands Mr 85 and 70 K. When the purified receptor was reduced, alkylated and treated with endo-..beta..-N-acetylglucosaminidase H, only one band was obtained at Mr of about 90 K.

  3. Ketamine: NMDA Receptors and Beyond

    OpenAIRE

    Zorumski, Charles F.; Izumi, Yukitoshi; Mennerick, Steven

    2016-01-01

    Human studies examining the effects of the dissociative anesthetic ketamine as a model for psychosis and as a rapidly acting antidepressant have spurred great interest in understanding ketamine's actions at molecular, cellular, and network levels. Although ketamine has unequivocal uncompetitive inhibitory effects on N-methyl-d-aspartate receptors (NMDARs) and may preferentially alter the function of NMDARs on interneurons, recent work has questioned whether block of NMDARs is critical for its...

  4. Assay for the glucagon receptor

    International Nuclear Information System (INIS)

    Rojas, F.J.; Birnbaumer, L.

    1985-01-01

    A new iodination procedure for glucagon using 1,3,4,6-tetracholoro-3α,6α-diphenylglycouril (Iodogen) as the oxidizing agent, and the subsequent separation in pure form of [ 125 I-Tyr 10 ]mono-iodoglucagon by reverse-phase high-pressure liquid chromatography (HPLC) over C 18 -μ Bondapak columns is described. The newly synthesized [ 125 I]mono-iodoglucagon is shown to be a suitable probe for studying structural and functional properties of glucagon receptors

  5. Keratinocyte cytokine and chemokine receptors.

    Science.gov (United States)

    Tüzün, Yalçin; Antonov, Meltem; Dolar, Neslihan; Wolf, Ronni

    2007-10-01

    Chemokines are a superfamily of small, secreted proteins that regulate cell traffic in homeostatic and inflammatory conditions. Keratinocytes synthesize many chemokines, including members of the CC and CXC subfamilies, such as regulated on activation of normal T-cell expressed and secreted, gamma-interferon inducible protein-10, monokine induced by gamma-interferon, and thymus- and activation-regulated chemokine. They also express some chemokine receptors that mediate the inflammatory or immune response by attracting various kinds of leukocytes.

  6. Insulin receptor in Drosophila melanogaster

    International Nuclear Information System (INIS)

    Petruzzelli, L.; Herrera, R.; Rosen, O.

    1986-01-01

    A specific, high affinity insulin receptor is present in both adult Drosophila and in Drosophila embryos. Wheat germ lectin-enriched extracts of detergent-solubilized membranes from embryos and adults bind insulin with a K/sub d/ of 15 nM. Binding is specific for insulin; micromolar concentrations of proinsulin, IGFI, and IGFII are required to displace bound 125 I-insulin. Insulin-dependent protein tyrosine kinase activity appears during embryogenesis. It is evident between 6 and 12 hours of development, peaks between 12 and 18 hours and falls in the adult. During 0-6 hours of embryogenesis, and in the adult, a specific protein band (Mr = 135,000) is crosslinked to 125 I-insulin. During 6-12 and 12-18 hours of embryogenesis stages in which insulin-dependent protein tyrosine kinase is high, an additional band (Mr = 100,000) becomes crosslinked to 125 I-insulin. Isolation and DNA sequence analysis of genomic clones encoding the Drosophila insulin receptor will be presented as will the characterization of insulin receptor mRNA's during development

  7. PAF receptor structure: a hypothesis.

    Science.gov (United States)

    Godfroid, J J; Dive, G; Lamotte-Brasseur, J; Batt, J P; Heymans, F

    1991-12-01

    Different hypotheses of the structure of platelet-activating factor (PAF) receptor based on structure-activity relationships of agonists and antagonists are reviewed. For an agonistic effect, strong hydrophobic interactions and an ether function are required in position-1 of the glycerol backbone; chain length limitations and steric hindrance demand a small group in position-2. The unusual structural properties of non-PAF-like antagonists required 3-D electrostatic potential calculations. This method applied to seven potent antagonists suggests a strong "Cache-orielles" (ear-muff) effect, i.e., two strong electronegative wells (isocontour at -10 Kcal/mole) are located at 180 degrees to each other and at a relatively constant distance. Initial consideration of the "Cache-oreilles" effect implied the structure of a bipolarized cylinder of 10-12 A diameter for the receptor. However, very recent results on studies with agonists and antagonists structurally similar to PAF suggest that the receptor may in fact be a multi-polarized cylinder.

  8. NGA/Insulin receptor scanning

    International Nuclear Information System (INIS)

    Kurtaran, A.; Virgolini, I.

    1994-01-01

    Tc-99m-galactosyl-neoglycoalbumin (NGA) is one of the first receptor-based radiopharmaceuticals which specifically recognizes the hepatic binding protein (HBP) located on the surface of the hepatocytes. The exclusive interactin of NGA with HBP provided the basis for a kinetic model for the evaluation hepatocellular function. During the last years we have used NGA in more than 300 patients with various liver diseases including liver cirrhosis (Stages Child A to Child C), viral hepatitis, and carcinomas. In these studies, the calculated HBP densities, after i.v.-injection of Tc-99m-NGA, significantly correlated with the clinical course of the diseases. Furthermore, similar to conventional Tc-colloid, NGA provided excellent demonstration of 'cold spots' for hepatic masses. In a further approach we used another hepatocyte receptor-seeking radioligand, I-123-Tyr-A14- insulin, and found, that its in vitro-binding to hepatocellular carcinomas is greatly enhanced over normal hepatic tissue. On this basis, we developed a double-tracer method using NGA and insulin in a single study. Thus, areas of 'cold spots' identifying hepatic masses on NGA scans, take up I-123-Tyr-A14-insulin immediately after i.v.-injection. This was true for hepatocellular hepatomas, but not for adenocarcinomas. In conclusion, NGA/insulin receptor scanning could be a novel and save method for the demonstration of hepatocellular hepatomas. (author)

  9. Lymphocyte receptors for pertussis toxin

    Energy Technology Data Exchange (ETDEWEB)

    Clark, C.G.; Armstrong, G.D. (Univ. of Alberta, Edmonton (Canada))

    1990-12-01

    We have investigated human T-lymphocyte receptors for pertussis toxin by affinity isolation and photoaffinity labeling procedures. T lymphocytes were obtained from peripheral human blood, surface iodinated, and solubilized in Triton X-100. The iodinated mixture was then passed through pertussis toxin-agarose, and the fractions were analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Autoradiography of the fixed, dried gels revealed several bands in the pertussis toxin-bound fraction that were not observed in fractions obtained from histone or fetuin-agarose. Further investigations employed a photoaffinity labeling reagent, sulfosuccinimidyl 2-(p-azido-salicylamido)-1,3'-dithiopropionate, to identify pertussis toxin receptors in freshly isolated peripheral blood monocytic cells, T lymphocytes, and Jurkat cells. In all three cell systems, the pertussis toxin affinity probe specifically labeled a single protein species with an apparent molecular weight of 70,000 that was not observed when the procedure was performed in the presence of excess unmodified pertussis toxin. A protein comparable in molecular weight to the one detected by the photoaffinity labeling technique was also observed among the species that bound to pertussis toxin-agarose. The results suggest that pertussis toxin may bind to a 70,000-Da receptor in human T lymphocytes.

  10. Nuclear receptors for thyroid hormones

    International Nuclear Information System (INIS)

    Ricketts, M.H.; Groenewald, J. de W.; Wilson, B.D.

    1980-01-01

    The thyroid hormones, T 3 and T 4 , modulate a vast number of metabolic processes in mammalian tissues. High affinity, low capacity binding sites for T 3 and T 4 have been demonstrated in cell nuclei of target organs using both in vivo and in vitro labelling techniques. The displacement of [ 125 I]T 3 from nuclear binding sites by thyroid hormone analogues correlates well with the thyromimetic activities of the analogues tested. Dose-response relationships between T 3 occupancy and growth hormone secretion as a function of free T 3 concentration have been established with the GH 1 cell line. The equilibrium dissociation constant of the equation which describes how T 3 binds to the nuclei of intact cells is essentially the same as the free T 3 concentration that elicits the half-maximal biological response of the hormone. It is becoming apparent that these nuclear binding sites represent specific thyroid hormone receptors, whose function may be to regulate gene activity in target tissues. This report concerns the binding of the rat liver nuclear receptor to duplex and random coil DNA as well as to non-mammalian and synthetic DNAs. We postulate that the receptor binds in vivo to native DNA in the minor groove of the DNA helix

  11. Complex GABAB receptor complexes: how to generate multiple functionally distinct units from a single receptor

    Directory of Open Access Journals (Sweden)

    Chanjuan eXU

    2014-02-01

    Full Text Available The main inhibitory neurotransmitter, GABA, acts on both ligand-gated and G protein-coupled receptors, the GABAA/C and GABAB receptors, respectively. The later play important roles in modulating many synapses, both at the pre- and post-synaptic levels, and are then still considered as interesting targets to treat a number of brain diseases, including addiction. For many years, several subtypes of GABAB receptors were expected, but cloning revealed only two genes that work in concert to generate a single type of GABAB receptor composed of two subunits. Here we will show that the signaling complexity of this unit receptor type can be largely increased through various ways, including receptor stoichiometry, subunit isoforms, membrane expression and localization, crosstalk with other receptors or interacting proteins. These recent data revealed how complexity of a receptor unit can be increased, observation that certainly are not unique to the GABAB receptor.

  12. The two-state dimer receptor model: a general model for receptor dimers.

    Science.gov (United States)

    Franco, Rafael; Casadó, Vicent; Mallol, Josefa; Ferrada, Carla; Ferré, Sergi; Fuxe, Kjell; Cortés, Antoni; Ciruela, Francisco; Lluis, Carmen; Canela, Enric I

    2006-06-01

    Nonlinear Scatchard plots are often found for agonist binding to G-protein-coupled receptors. Because there is clear evidence of receptor dimerization, these nonlinear Scatchard plots can reflect cooperativity on agonist binding to the two binding sites in the dimer. According to this, the "two-state dimer receptor model" has been recently derived. In this article, the performance of the model has been analyzed in fitting data of agonist binding to A(1) adenosine receptors, which are an example of receptor displaying concave downward Scatchard plots. Analysis of agonist/antagonist competition data for dopamine D(1) receptors using the two-state dimer receptor model has also been performed. Although fitting to the two-state dimer receptor model was similar to the fitting to the "two-independent-site receptor model", the former is simpler, and a discrimination test selects the two-state dimer receptor model as the best. This model was also very robust in fitting data of estrogen binding to the estrogen receptor, for which Scatchard plots are concave upward. On the one hand, the model would predict the already demonstrated existence of estrogen receptor dimers. On the other hand, the model would predict that concave upward Scatchard plots reflect positive cooperativity, which can be neither predicted nor explained by assuming the existence of two different affinity states. In summary, the two-state dimer receptor model is good for fitting data of binding to dimeric receptors displaying either linear, concave upward, or concave downward Scatchard plots.

  13. Characterization of astrocytic and neuronal benzodiazepine receptors

    Energy Technology Data Exchange (ETDEWEB)

    Bender, A.S.

    1988-01-01

    Primary cultures of astrocytes and neurons express benzodiazepine receptors. Neuronal benzodiazepine receptors were of high-affinity, K{sub D} values were 7.5-43 nM and the densities of receptors (B{sub max}) were 924-4131 fmol/mg protein. Astrocytes posses a high-affinity benzodiazepine receptor, K{sub D} values were 6.6-13 nM. The B{sub max} values were 6,033-12,000 fmol/mg protein. The pharmacological profile of the neuronal benzodiazepine receptor was that of the central-type benzodiazepine receptor, where clonazepam has a high-affinity and Ro 5-4864 (4{prime}-chlorodiazepam) has a low-affinity. Whereas astrocytic benzoidazepine receptor was characteristic of the so called peripheral-type benzodiazepine receptors, which shows a high-affinity towards Ro 5-4863, and a low-affinity towards clonazepam. The astrocytic benzodiazepine receptors was functionally correlated with voltage dependent calcium channels, since dihydropyridines and benzodiazepines interacted with ({sup 3}H) diazepam and ({sup 3}H) nitrendipine receptors with the same rank order of potency, showing a statistically significant correlation. No such correlation was observed in neurons.

  14. Localization of mineralocorticoid receptors at mammalian synapses.

    Directory of Open Access Journals (Sweden)

    Eric M Prager

    Full Text Available In the brain, membrane associated nongenomic steroid receptors can induce fast-acting responses to ion conductance and second messenger systems of neurons. Emerging data suggest that membrane associated glucocorticoid and mineralocorticoid receptors may directly regulate synaptic excitability during times of stress when adrenal hormones are elevated. As the key neuron signaling interface, the synapse is involved in learning and memory, including traumatic memories during times of stress. The lateral amygdala is a key site for synaptic plasticity underlying conditioned fear, which can both trigger and be coincident with the stress response. A large body of electrophysiological data shows rapid regulation of neuronal excitability by steroid hormone receptors. Despite the importance of these receptors, to date, only the glucocorticoid receptor has been anatomically localized to the membrane. We investigated the subcellular sites of mineralocorticoid receptors in the lateral amygdala of the Sprague-Dawley rat. Immunoblot analysis revealed the presence of mineralocorticoid receptors in the amygdala. Using electron microscopy, we found mineralocorticoid receptors expressed at both nuclear including: glutamatergic and GABAergic neurons and extra nuclear sites including: presynaptic terminals, neuronal dendrites, and dendritic spines. Importantly we also observed mineralocorticoid receptors at postsynaptic membrane densities of excitatory synapses. These data provide direct anatomical evidence supporting the concept that, at some synapses, synaptic transmission is regulated by mineralocorticoid receptors. Thus part of the stress signaling response in the brain is a direct modulation of the synapse itself by adrenal steroids.

  15. Protein Connectivity in Chemotaxis Receptor Complexes.

    Directory of Open Access Journals (Sweden)

    Stephan Eismann

    2015-12-01

    Full Text Available The chemotaxis sensory system allows bacteria such as Escherichia coli to swim towards nutrients and away from repellents. The underlying pathway is remarkably sensitive in detecting chemical gradients over a wide range of ambient concentrations. Interactions among receptors, which are predominantly clustered at the cell poles, are crucial to this sensitivity. Although it has been suggested that the kinase CheA and the adapter protein CheW are integral for receptor connectivity, the exact coupling mechanism remains unclear. Here, we present a statistical-mechanics approach to model the receptor linkage mechanism itself, building on nanodisc and electron cryotomography experiments. Specifically, we investigate how the sensing behavior of mixed receptor clusters is affected by variations in the expression levels of CheA and CheW at a constant receptor density in the membrane. Our model compares favorably with dose-response curves from in vivo Förster resonance energy transfer (FRET measurements, demonstrating that the receptor-methylation level has only minor effects on receptor cooperativity. Importantly, our model provides an explanation for the non-intuitive conclusion that the receptor cooperativity decreases with increasing levels of CheA, a core signaling protein associated with the receptors, whereas the receptor cooperativity increases with increasing levels of CheW, a key adapter protein. Finally, we propose an evolutionary advantage as explanation for the recently suggested CheW-only linker structures.

  16. Amphipathic benzenes are designed inhibitors of the estrogen receptor alpha/steroid receptor coactivator interaction.

    Science.gov (United States)

    Gunther, Jillian R; Moore, Terry W; Collins, Margaret L; Katzenellenbogen, John A

    2008-05-16

    We report here on the design, synthesis, and evaluation of small molecule inhibitors of the interaction between a steroid receptor coactivator and estrogen receptor alpha. These inhibitors are based upon an amphipathic benzene scaffold whose hydrophobic face mimics the leucine-rich alpha-helical consensus sequence on the steroid receptor coactivators that interacts with a shallow groove on estrogen receptor alpha. Several of these molecules are among the most potent inhibitors of this interaction described to date and are active at low micromolar concentrations in both in vitro models of estrogen receptor action and in cell-based assays of estrogen receptor-mediated coactivator interaction and transcription.

  17. Activation of glucocorticoid receptors increases 5-HT2A receptor levels

    DEFF Research Database (Denmark)

    Trajkovska, Viktorija; Kirkegaard, Lisbeth; Krey, Gesa

    2009-01-01

    of depression is unknown. In mice with altered glucocorticoid receptor (GR) expression we investigated 5-HT2A receptor levels by Western blot and 3H-MDL100907 receptor binding. Serotonin fibre density was analyzed by stereological quantification of serotonin transporter immunopositive fibers. To establish...... an effect of GR activation on 5-HT2A levels, mature organotypic hippocampal cultures were exposed to corticosterone with or without GR antagonist mifepristone and mineralocorticoid receptor (MR) antagonist spironolactone. In GR under-expressing mice, hippocampal 5-HT2A receptor protein levels were decreased...... in dorsal hippocampus (77 +/- 35%, p effect of GR activation on 5-HT2A receptor...

  18. Receptor Tyrosine Kinases in Drosophila Development

    Science.gov (United States)

    Sopko, Richelle; Perrimon, Norbert

    2013-01-01

    Tyrosine phosphorylation plays a significant role in a wide range of cellular processes. The Drosophila genome encodes more than 20 receptor tyrosine kinases and extensive studies in the past 20 years have illustrated their diverse roles and complex signaling mechanisms. Although some receptor tyrosine kinases have highly specific functions, others strikingly are used in rather ubiquitous manners. Receptor tyrosine kinases regulate a broad expanse of processes, ranging from cell survival and proliferation to differentiation and patterning. Remarkably, different receptor tyrosine kinases share many of the same effectors and their hierarchical organization is retained in disparate biological contexts. In this comprehensive review, we summarize what is known regarding each receptor tyrosine kinase during Drosophila development. Astonishingly, very little is known for approximately half of all Drosophila receptor tyrosine kinases. PMID:23732470

  19. Acetylcholine receptors in the human retina

    International Nuclear Information System (INIS)

    Hutchins, J.B.; Hollyfield, J.G.

    1985-01-01

    Evidence for a population of acetylcholine (ACh) receptors in the human retina is presented. The authors have used the irreversible ligand 3 H-propylbenzilylcholine mustard ( 3 H-PrBCM) to label muscarinic receptors. 3 H- or 125 I-alpha-bungarotoxin (alpha-BTx) was used to label putative nicotinic receptors. Muscarinic receptors are apparently present in the inner plexiform layer of the retina. Autoradiographic grain densities are reduced in the presence of saturating concentrations of atropine, quinuclidinyl benzilate or scopolamine; this indicates that 3 H-PrBCM binding is specific for a population of muscarinic receptors in the human retina. Binding sites for radiolabeled alpha-BTx are found predominantly in the inner plexiform layer of the retina. Grain densities are reduced in the presence of d-tubocurarine, indicating that alpha-BTx may bind to a pharmacologically relevant nicotinic ACh receptor. This study provides evidence for cholinergic neurotransmission in the human retina

  20. Characteristic molecular vibrations of adenosine receptor ligands.

    Science.gov (United States)

    Chee, Hyun Keun; Yang, Jin-San; Joung, Je-Gun; Zhang, Byoung-Tak; Oh, S June

    2015-02-13

    Although the regulation of membrane receptor activation is known to be crucial for molecular signal transduction, the molecular mechanism underlying receptor activation is not fully elucidated. Here we study the physicochemical nature of membrane receptor behavior by investigating the characteristic molecular vibrations of receptor ligands using computational chemistry and informatics methods. By using information gain, t-tests, and support vector machines, we have identified highly informative features of adenosine receptor (AdoR) ligand and corresponding functional amino acid residues such as Asn (6.55) of AdoR that has informative significance and is indispensable for ligand recognition of AdoRs. These findings may provide new perspectives and insights into the fundamental mechanism of class A G protein-coupled receptor activation. Copyright © 2015 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

  1. Subtype selective kainic acid receptor agonists

    DEFF Research Database (Denmark)

    Bunch, Lennart; Krogsgaard-Larsen, Povl

    2009-01-01

    (S)-Glutamic acid (Glu) is the major excitatory neurotransmitter in the mammalian central nervous system, activating the plethora of glutamate receptors (GluRs). In broad lines, the GluRs are divided into two major classes: the ionotropic Glu receptors (iGluRs) and the metabotropic Glu receptors (m......GluRs). Within the iGluRs, five subtypes (KA1, KA2, iGluR5-7) show high affinity and express full agonist activity upon binding of the naturally occurring amino acid kainic acid (KA). Thus these receptors have been named the KA receptors. This review describes all-to our knowledge-published KA receptor agonists...

  2. Androgen receptor in estrogen receptor positive breast cancer: Beyond expression.

    Science.gov (United States)

    Basile, Debora; Cinausero, Marika; Iacono, Donatella; Pelizzari, Giacomo; Bonotto, Marta; Vitale, Maria Grazia; Gerratana, Lorenzo; Puglisi, Fabio

    2017-12-01

    In recent years, new therapeutic approaches have reshaped the overall strategy of breast cancer (BC) treatment and have markedly improved patient survival. This is, in part, due to novel therapies for estrogen receptor (ER)-positive BC. Unfortunately, many patients present de novo resistance to these therapies or develop an acquired resistance over time. Therefore, research is now focused on discovering new molecular targets to overcome these resistances. Interestingly, preclinical and clinical studies have shown a critical role for the cross-talk between androgen receptor (AR) and ER in luminal-like BC. AR is expressed in >60% of BC and in up to 90% of ERα-positive tumors. Multiple studies suggest that AR is associated with a favorable prognosis. However, AR overexpression and, in particular, the high AR:ER ratio, seem to be involved in resistance to hormonal treatment. In this setting, a group of BCs could benefit from AR-inhibitors; nevertheless, some ER-positive BC patients do not seem to benefit from this strategy. Therefore, it is crucial to identify biomarkers that would enable the selection of patients who might benefit from combination treatment with ER and AR inhibitors. Copyright © 2017 Elsevier Ltd. All rights reserved.

  3. Xenobiotics and the Glucocorticoid Receptor.

    Science.gov (United States)

    Gulliver, Linda S M

    2017-03-15

    Glucocorticoid Receptor (GR) is present in virtually every human cell type. Representing a nuclear receptor superfamily, GR has several different isoforms essentially acting as ligand-dependent transcription factors, regulating glucocorticoid-responsive gene expression in both a positive and a negative manner. Although the natural ligand of the Glucocorticoid Receptor, glucocorticoids (GC) represent only some of the multiple ligands for GR. Xenobiotics, ubiquitous in the environment, bind to GR and are also capable of activating or repressing GR gene expression, thereby modulating GR cell and tissue-specific downstream effects in a multitude of ways that include responses to inflammatory, allergic, metabolic, neoplastic and autoimmune processes. Many xenobiotics, if inadequately metabolized by xenobiotic metabolizing enzymes and not wholly eliminated, could have deleterious toxic effects with potentially lethal consequences. This review examines GR, the genomic and non-genomic actions of natural and synthetic GC and the body's handling of xenobiotic compounds, before reviewing what is presently known about GR's interactions with many of the more commonly encountered and some of the less well known GR-associated xenobiotics. GR promiscuity and crosstalk with other signaling pathways is discussed, alongside novel roles for GR that include mood disorder and addiction. A knowledge of GR interactions with xenobiotics is increasingly relevant when considering aging populations and the related prevalence of neoplastic disease, together with growing concerns around human exposure to mixtures of chemicals in the environment. Furthermore, escalating rates of obesity, Type 2 diabetes; autoimmune, allergy, addiction and mood disorder-related pathologies, require novel targeted interventions and GR appears a promising pharmacological candidate. Copyright © 2017 Elsevier Inc. All rights reserved.

  4. NUREBASE: database of nuclear hormone receptors

    OpenAIRE

    Duarte, Jorge; Perrière, Guy; Laudet, Vincent; Robinson-Rechavi, Marc

    2002-01-01

    Nuclear hormone receptors are an abundant class of ligand activated transcriptional regulators, found in varying numbers in all animals. Based on our experience of managing the official nomenclature of nuclear receptors, we have developed NUREBASE, a database containing protein and DNA sequences, reviewed protein alignments and phylogenies, taxonomy and annotations for all nuclear receptors. The reviewed NUREBASE is completed by NUREBASE_DAILY, automatically updated every 24 h. Both databases...

  5. Progesterone receptor modulators in breast cancer

    OpenAIRE

    WIEHLE, Ronald D.

    2015-01-01

    Breast cancer has been treated successfully with selective estrogen receptor antagonists (SERMs) such as tamoxifen, receptor-depleting agents such as fulvestrant, and aromatase inhibitors such as anastrozole. Selective progesterone receptor modulators (SPRMs or PRMs) have not been studied as much and are currently under investigation for inhibition of mammary carcinogenesis in animal models and breast cancer prevention trials in women. They might follow tamoxifen and aromatase inhibitors in t...

  6. Hemoglobin and heme scavenger receptors

    DEFF Research Database (Denmark)

    Nielsen, Marianne Jensby; Møller, Holger Jon; Moestrup, Søren Kragh

    2010-01-01

    Heme, the functional group of hemoglobin, myoglobin, and other hemoproteins, is a highly toxic substance when it appears in the extracellular milieu. To circumvent potential harmful effects of heme from hemoproteins released during physiological or pathological cell damage (such as hemolysis...... and rhabdomyolysis), specific high capacity scavenging systems have evolved in the mammalian organism. Two major systems, which essentially function in a similar way by means of a circulating latent plasma carrier protein that upon ligand binding is recognized by a receptor, are represented by a) the hemoglobin...

  7. CERAPP: Collaborative Estrogen Receptor Activity Prediction Project

    Data.gov (United States)

    U.S. Environmental Protection Agency — Data from a large-scale modeling project called CERAPP (Collaborative Estrogen Receptor Activity Prediction Project) demonstrating using predictive computational...

  8. Human dopamine receptor and its uses

    Energy Technology Data Exchange (ETDEWEB)

    Civelli, Olivier (Portland, OR); Van Tol, Hubert Henri-Marie (Toronto, CA)

    1999-01-01

    The present invention is directed toward the isolation, characterization and pharmacological use of the human D4 dopamine receptor. The nucleotide sequence of the gene corresponding to this receptor and alleleic variant thereof are provided by the invention. The invention also includes recombinant eukaryotic expression constructs capable of expressing the human D4 dopamine receptor in cultures of transformed eukaryotic cells. The invention provides cultures of transformed eukaryotic cells which synthesize the human D4 dopamine receptor, and methods for characterizing novel psychotropic compounds using such cultures.

  9. Characterization of the chicken muscle insulin receptor

    International Nuclear Information System (INIS)

    Adamo, M.; Simon, J.; Rosebrough, R.W.; McMurtry, J.P.; Steele, N.C.; LeRoith, D.

    1987-01-01

    Insulin receptors are present in chicken skeletal muscle. Crude membrane preparations demonstrated specific 125 I-insulin binding. The nonspecific binding was high (36-55% of total binding) and slightly lower affinity receptors were found than are typically observed for crude membrane insulin binding in other chicken tissues. Affinity crosslinking of 125 I-insulin to crude membranes revealed insulin receptor alpha-subunits of Mr 128K, intermediate between those of liver (134K) and brain (124K). When solubilized and partially purified on wheat germ agglutinin (WGA) affinity columns, chicken muscle insulin receptors exhibited typical high affinity binding, with approximately 10(-10) M unlabeled insulin producing 50% inhibition of the specific 125 I-insulin binding. WGA purified chicken muscle insulin receptors also exhibited insulin-stimulated autophosphorylation of the beta-subunit, which appeared as phosphorylated bands of 92- and 81K. Both bands were immunoprecipitated by anti-receptor antiserum (B10). WGA purified membranes also demonstrated dose-dependent insulin-stimulated phosphorylation of the exogenous substrate poly(Glu,Tyr)4:1. However, unlike chicken liver, chicken muscle insulin receptor number and tyrosine kinase activity were unaltered by 48 hr of fasting or 48 hr of fasting and 24 hr of refeeding. Thus, despite the presence of insulin receptors in chicken muscle showing normal coupling to receptor tyrosine kinase activity, nutritional alterations modulate these parameters in a tissue-specific manner in chickens

  10. Evolution of Class I cytokine receptors

    Science.gov (United States)

    Liongue, Clifford; Ward, Alister C

    2007-01-01

    Background The Class I cytokine receptors have a wide range of actions, including a major role in the development and function of immune and blood cells. However, the evolution of the genes encoding them remains poorly understood. To address this we have used bioinformatics to analyze the Class I receptor repertoire in sea squirt (Ciona intestinalis) and zebrafish (Danio rerio). Results Only two Class I receptors were identified in sea squirt, one with homology to the archetypal GP130 receptor, and the other with high conservation with the divergent orphan receptor CLF-3. In contrast, 36 Class I cytokine receptors were present in zebrafish, including representative members for each of the five structural groups found in mammals. This allowed the identification of 27 core receptors belonging to the last common ancestor of teleosts and mammals. Conclusion This study suggests that the majority of diversification of this receptor family occurred after the divergence of urochordates and vertebrates approximately 794 million years ago (MYA), but before the divergence of ray-finned from lobe-finned fishes around 476 MYA. Since then, only relatively limited lineage-specific diversification within the different Class I receptor structural groups has occurred. PMID:17640376

  11. Identification and mechanism of ABA receptor antagonism

    KAUST Repository

    Melcher, Karsten

    2010-08-22

    The phytohormone abscisic acid (ABA) functions through a family of fourteen PYR/PYL receptors, which were identified by resistance to pyrabactin, a synthetic inhibitor of seed germination. ABA activates these receptors to inhibit type 2C protein phosphatases, such as ABI1, yet it remains unclear whether these receptors can be antagonized. Here we demonstrate that pyrabactin is an agonist of PYR1 and PYL1 but is unexpectedly an antagonist of PYL2. Crystal structures of the PYL2-pyrabactin and PYL1-pyrabactin-ABI1 complexes reveal the mechanism responsible for receptor-selective activation and inhibition, which enables us to design mutations that convert PYL1 to a pyrabactin-inhibited receptor and PYL2 to a pyrabactin-activated receptor and to identify new pyrabactin-based ABA receptor agonists. Together, our results establish a new concept of ABA receptor antagonism, illustrate its underlying mechanisms and provide a rational framework for discovering novel ABA receptor ligands. © 2010 Nature America, Inc. All rights reserved.

  12. ABA Receptors: Past, Present and Future

    Energy Technology Data Exchange (ETDEWEB)

    Guo, Jianjun [Harvard University; Yang, Xiaohan [ORNL; Weston, David [ORNL; Chen, Jay [ORNL

    2011-01-01

    Abscisic acid (ABA) is the key plant stress hormone. Consistent with the earlier studies in support of the presence of both membrane- and cytoplasm-localized ABA receptors, recent studies have identified multiple ABA receptors located in various subcellular locations. These include a chloroplast envelope-localized receptor (the H subunit of Chloroplast Mg2+-chelatase/ABA Receptor), two plasma membrane-localized receptors (G-protein Coupled Receptor 2 and GPCR-type G proteins), and one cytosol/nucleus-localized Pyrabactin Resistant (PYR)/PYR-Like (PYL)/Regulatory Component of ABA Receptor 1 (RCAR). Although the downstream molecular events for most of the identified ABA receptors are currently unknown, one of them, PYR/PYL/RACR was found to directly bind and regulate the activity of a long-known central regulator of ABA signaling, the A-group protein phosphatase 2C (PP2C). Together with the Sucrose Non-fermentation Kinase Subfamily 2 (SnRK2s) protein kinases, a central signaling complex (ABA-PYR-PP2Cs-SnRK2s) that is responsible for ABA signal perception and transduction is supported by abundant genetic, physiological, biochemical and structural evidence. The identification of multiple ABA receptors has advanced our understanding of ABA signal perception and transduction while adding an extra layer of complexity.

  13. Amphipathic Benzenes Are Designed Inhibitors of the Estrogen Receptor α/Steroid Receptor Coactivator Interaction

    OpenAIRE

    Gunther, Jillian R.; Moore, Terry W.; Collins, Margaret L.; Katzenellenbogen, John A.

    2008-01-01

    We report here on the design, synthesis and evaluation of small molecule inhibitors of the interaction between a steroid receptor coactivator and estrogen receptor α. These inhibitors are based upon an amphipathic benzene scaffold whose hydrophobic face mimics the leucine-rich α-helical consensus sequence on the steroid receptor coactivators that interacts with a shallow groove on estrogen receptor α. Several of these molecules are among the most potent inhibitors of this interaction describe...

  14. Hypothyroidism Affects D2 Receptor-mediated Breathing without altering D2 Receptor Expression

    OpenAIRE

    Schlenker, Evelyn H.; Rio, Rodrigo Del; Schultz, Harold D.

    2014-01-01

    Bromocriptine depressed ventilation in air and D2 receptor expression in the nucleus tractus solitaries (NTS) in male hypothyroid hamsters. Here we postulated that in age- matched hypothyroid female hamsters, the pattern of D2 receptor modulation of breathing and D2 receptor expression would differ from those reported in hypothyroid males. In females hypothyroidism did not affect D2 receptor protein levels in the NTS, carotid bodies or striatum. Bromocriptine, but not carmoxirole (a periphera...

  15. Hierarchical Phosphorylation of δ-Opioid Receptor Regulates Agonist-induced Receptor Desensitization and Internalization*

    OpenAIRE

    Maestri-El Kouhen, Odile; Wang, Guilin; Solberg, Jonathan; Erickson, Laurie J.; Law, Ping-Yee; Loh, Horace H.

    2000-01-01

    Treatment of HEK293 cells expressing the δ-opioid receptor with agonist [d-Pen2,5]enkephalin (DPDPE) resulted in the rapid phosphorylation of the receptor. We constructed several mutants of the potential phosphorylation sites (Ser/Thr) at the carboxyl tail of the receptor in order to delineate the receptor phosphorylation sites and the agonist-induced desensitization and internalization. The Ser and Thr were substituted to alanine, and the corresponding mutants were transiently and stably exp...

  16. The repertoire of trace amine G-protein-coupled receptors

    DEFF Research Database (Denmark)

    Gloriam, David E.; Bjarnadóttir, Thóra K; Yan, Yi-Lin

    2005-01-01

    eukaryotic species for receptors similar to the mammalian trace amine (TA) receptor subfamily. We identified 18 new receptors in rodents that are orthologous to the previously known TA-receptors. Remarkably, we found 57 receptors (and 40 pseudogenes) of this type in the zebrafish (Danio rerio), while fugu...

  17. One for all: the receptor-associated kinase BAK1.

    NARCIS (Netherlands)

    Chinchilla, D.; Shan, L.; He, P.; Vries, de S.C.; Kemmerling, B.

    2009-01-01

    The plant receptor kinase BAK1/SERK3 has been identified as a partner of ligand-binding leucine-rich repeat receptor kinases, in particular the brassinosteroid receptor BRI1 and the immune receptor FLS2. BAK1 positively regulates BRI1 receptor function via physical interaction and

  18. The G protein-coupled receptor, class C, group 6, subtype A (GPRC6A) receptor

    DEFF Research Database (Denmark)

    Clemmensen, C; Smajilovic, S; Wellendorph, P

    2014-01-01

    GPRC6A (G protein-coupled receptor, class C, group 6, subtype A) is a class C G protein-coupled receptor, that has been cloned from human, mouse and rat. Several groups have shown that the receptor is activated by a range of basic and small aliphatic L-α-amino acids of which L-arginine, L-lysine...

  19. The substance P/NK-1 receptor system: NK-1 receptor antagonists ...

    Indian Academy of Sciences (India)

    2015-04-27

    Apr 27, 2015 ... The substance P (SP)/neurokinin (NK)-1 receptor system plays an important role in cancer. SP promotes the ... NK-1 receptor may be a promising target in the treatment of cancer; NK-1 receptor antagonists could act as specific ...... mycin, ifosfamide, cisplatin) in MG-63 human osteosarcoma cells, but not in ...

  20. Interaction of epidermal growth factor receptors with the cytoskeleton is related to receptor clustering

    NARCIS (Netherlands)

    van Belzen, N.; Spaargaren, M.; Verkleij, A. J.; Boonstra, J.

    1990-01-01

    Recently it has been established that cytoskeleton-associated epidermal growth factor (EGF) receptors are predominantly of the high-affinity class and that EGF induces a recruitment of low-affinity receptors to the cytoskeleton. The nature of this EGF-induced receptor-cytoskeleton interaction,

  1. Posttransplant chimeric antigen receptor therapy.

    Science.gov (United States)

    Smith, Melody; Zakrzewski, Johannes; James, Scott; Sadelain, Michel

    2018-03-08

    Therapeutic T-cell engineering is emerging as a powerful approach to treat refractory hematological malignancies. Its most successful embodiment to date is based on the use of second-generation chimeric antigen receptors (CARs) targeting CD19, a cell surface molecule found in most B-cell leukemias and lymphomas. Remarkable complete remissions have been obtained with autologous T cells expressing CD19 CARs in patients with relapsed, chemo-refractory B-cell acute lymphoblastic leukemia, chronic lymphocytic leukemia, and non-Hodgkin lymphoma. Allogeneic CAR T cells may also be harnessed to treat relapse after allogeneic hematopoietic stem cell transplantation. However, the use of donor T cells poses unique challenges owing to potential alloreactivity. We review different approaches to mitigate the risk of causing or aggravating graft-versus-host disease (GVHD), including CAR therapies based on donor leukocyte infusion, virus-specific T cells, T-cell receptor-deficient T cells, lymphoid progenitor cells, and regulatory T cells. Advances in CAR design, T-cell selection and gene editing are poised to enable the safe use of allogeneic CAR T cells without incurring GVHD. © 2018 by The American Society of Hematology.

  2. Microarray-Based Determination of Estrogen Receptor, Progesterone Receptor, and HER2 Receptor Status in Breast Cancer

    NARCIS (Netherlands)

    Roepman, Paul; Horlings, Hugo M.; Krijgsman, Oscar; Kok, Marleen; Bueno-de-Mesquita, Jolien M.; Bender, Richard; Linn, Sabine C.; Glas, Annuska M.; van de Vijver, Marc J.

    2009-01-01

    Purpose: The level of estrogen receptor (ER), progesterone receptor (PR), and HER2 aids in the determination of prognosis and treatment of breast cancer. Immunohistochemistry is currently the predominant method for assessment, but differences in methods and interpretation can substantially affect

  3. The lactate receptor, G-protein-coupled receptor 81/hydroxycarboxylic acid receptor 1

    DEFF Research Database (Denmark)

    Morland, Cecilie; Lauritzen, Knut Huso; Puchades, Maja

    2015-01-01

    , and schizophrenia and in the deposition of phosphorylated tau protein in Alzheimer's disease. HCAR1 could serve to ameliorate these conditions and might also act through downstream mechanisms other than cAMP. Lactate exits cells through monocarboxylate transporters in an equilibrating manner and through astrocyte...... anion channels activated by depolarization. In addition to locally produced lactate, lactate produced by exercising muscle as well as exogenous HCAR1 agonists, e.g., from fruits and berries, might activate the receptor on cerebral blood vessels and brain cells....

  4. A bioluminescence resonance energy transfer 2 (BRET2) assay for monitoring seven transmembrane receptor and insulin receptor crosstalk

    DEFF Research Database (Denmark)

    Sanni, Samra Joke; Kulahin, Nikolaj; Jorgensen, Rasmus

    2017-01-01

    The angiotensin AT1 receptor is a seven transmembrane (7TM) receptor, which mediates the regulation of blood pressure. Activation of angiotensin AT1 receptor may lead to impaired insulin signaling indicating crosstalk between angiotensin AT1 receptor and insulin receptor signaling pathways. To el...

  5. Cannabinoid 2 Receptor- and Beta Arrestin 2-Dependent Upregulation of Serotonin 2A Receptors

    OpenAIRE

    Franklin, J.M.; Vasiljevik, T.; Prisinzano, T.E.; Carrasco, G.A.

    2012-01-01

    Recent evidence suggests that cannabinoid receptor agonists may regulate serotonin 2A (5-HT2A) receptor neurotransmission in the brain, although no molecular mechanism has been identified. Here, we present experimental evidence that sustained treatment with a non-selective cannabinoid agonist (CP 55,940) or selective CB2 receptor agonists (JWH 133 or GP 1a) upregulate 5-HT2A receptors in a neuronal cell line. Furthermore, this cannabinoid receptor agonist-induced upregulation of 5-HT2A recept...

  6. Identifying the receptor subtype selectivity of retinoid X and retinoic acid receptors via quantum mechanics.

    Science.gov (United States)

    Tsuji, Motonori; Shudo, Koichi; Kagechika, Hiroyuki

    2017-03-01

    Understanding and identifying the receptor subtype selectivity of a ligand is an important issue in the field of drug discovery. Using a combination of classical molecular mechanics and quantum mechanical calculations, this report assesses the receptor subtype selectivity for the human retinoid X receptor (hRXR) and retinoic acid receptor (hRAR) ligand-binding domains (LBDs) complexed with retinoid ligands. The calculated energies show good correlation with the experimentally reported binding affinities. The technique proposed here is a promising method as it reveals the origin of the receptor subtype selectivity of selective ligands.

  7. In vivo studies of opiate receptors

    International Nuclear Information System (INIS)

    Frost, J.J.; Dannals, R.F.; Duelfer, T.; Burns, H.D.; Ravert, H.T.; Langstroem, B.; Balasubramanian, V.; Wagner, H.N. Jr.

    1984-01-01

    To study opiate receptors noninvasively in vivo using positron emission tomography, techniques for preferentially labeling opiate receptors in vivo can be used. The rate at which receptor-bound ligand clears from the brain in vivo can be predicted by measuring the equilibrium dissociation constant (KD) at 37 degrees C in the presence of 100 mM sodium chloride and 100 microM guanyl-5'-imidodiphosphate, the drug distribution coefficient, and the molecular weight. A suitable ligand for labeling opiate receptors in vivo is diprenorphine, which binds to mu, delta, and kappa receptors with approximately equal affinity in vitro. However, in vivo diprenorphine may bind predominantly to one opiate receptor subtype, possibly the mu receptor. To predict the affinity for binding to the opiate receptor, a Hansch correlation was determined between the 50% inhibitory concentration for a series of halogen-substituted fentanyl analogs and electronic, lipophilic, and steric parameters. Radiochemical methods for the synthesis of carbon-11-labeled diprenorphine and lofentanil are presented

  8. In vivo studies of opiate receptors

    Energy Technology Data Exchange (ETDEWEB)

    Frost, J.J.; Dannals, R.F.; Duelfer, T.; Burns, H.D.; Ravert, H.T.; Langstroem, B.; Balasubramanian, V.; Wagner, H.N. Jr.

    1984-01-01

    To study opiate receptors noninvasively in vivo using positron emission tomography, techniques for preferentially labeling opiate receptors in vivo can be used. The rate at which receptor-bound ligand clears from the brain in vivo can be predicted by measuring the equilibrium dissociation constant (KD) at 37 degrees C in the presence of 100 mM sodium chloride and 100 microM guanyl-5'-imidodiphosphate, the drug distribution coefficient, and the molecular weight. A suitable ligand for labeling opiate receptors in vivo is diprenorphine, which binds to mu, delta, and kappa receptors with approximately equal affinity in vitro. However, in vivo diprenorphine may bind predominantly to one opiate receptor subtype, possibly the mu receptor. To predict the affinity for binding to the opiate receptor, a Hansch correlation was determined between the 50% inhibitory concentration for a series of halogen-substituted fentanyl analogs and electronic, lipophilic, and steric parameters. Radiochemical methods for the synthesis of carbon-11-labeled diprenorphine and lofentanil are presented.

  9. The Relationship of Erythropoietin Receptor Expression and ...

    African Journals Online (AJOL)

    2018-04-04

    Apr 4, 2018 ... A critical role of erythropoietin receptor in neurogenesis and post‑stroke recovery. J Neurosci 2006;26:1269‑74. 4. Ribatti D, Poliani PL, Longo V, Mangieri D, Nico B,. Vacca A. Erythropoietin/erythropoietin receptor system is involved in angiogenesis in human neuroblastoma. Histopathology 2007 ...

  10. Progesterone Receptor Scaffolding Function in Breast Cancer

    Science.gov (United States)

    2012-10-01

    response. PR are expressed in multiple human tissues including the uterus, mammary gland , brain, pancreas, thymus , bone, ovary, testes, and in the...ABSTRACT Progesterone receptors (PR) are critical mediators of mammary gland development and contribute to breast cancer progression. Progestin...receptors (PR) are critical for massive breast epithelial cell expansion during mammary gland development and contribute to breast cancer progression

  11. Structural Studies of Nicotinic Acetylcholine Receptors

    DEFF Research Database (Denmark)

    Shahsavar, Azadeh; Gajhede, Michael; Kastrup, Jette

    2016-01-01

    Nicotinic acetylcholine receptors (nAChRs) are members of the pentameric ligand-gated ion channel superfamily that play important roles in control of neurotransmitter release in the central and peripheral nervous system. These receptors are important therapeutic targets for development of drugs...

  12. Docking to flexible nicotinic acetylcholine receptors

    DEFF Research Database (Denmark)

    Sander, Tommy; Bruun, Anne T; Balle, Thomas

    2010-01-01

    Computational docking to nicotinic acetylcholine receptors (nAChRs) and other members of the Cys-loop receptor family is complicated by the flexibility of the so-called C-loop. As observed in the large number of published crystal structures of the acetylcholine binding protein (AChBP), a structural...

  13. Structural Mapping of Adenosine Receptor Mutations

    DEFF Research Database (Denmark)

    Jespers, Willem; Schiedel, Anke C; Heitman, Laura H

    2018-01-01

    The four adenosine receptors (ARs), A1, A2A, A2B, and A3, constitute a subfamily of G protein-coupled receptors (GPCRs) with exceptional foundations for structure-based ligand design. The vast amount of mutagenesis data, accumulated in the literature since the 1990s, has been recently supplemente...

  14. Interactions of Rodent Coronaviruses with Cellular Receptors

    Science.gov (United States)

    2016-05-08

    bluecomb disease). b. Other diseases caused by corooaviruses inc lude infectious peritonitis, r!¥lting, nephritis , pancreatitis , parotitis, and...homology with the MEV receptor, perhaps a different member of the CEA family such as the rat pregnancy specific glycoprotein could serve as a receptor

  15. Receptors, G proteins, and their interactions

    NARCIS (Netherlands)

    Hollmann, Markus W.; Strumper, Danja; Herroeder, Susanne; Durieux, Marcel E.

    2005-01-01

    Membrane receptors coupling to intracellular G proteins (G protein-coupled receptors) form one of the major classes of membrane signaling proteins. They are of great importance to the practice of anesthesiology because they are involved in many systems of relevance to the specialty (cardiovascular

  16. Lipoprotein receptors in cultured bovine endothelial cells

    International Nuclear Information System (INIS)

    Struempfer, A.E.M.

    1983-07-01

    In this study, receptors that may be involved in the uptake of low density lipoproteins (LDL) and low density lipoproteins which have been modified by acetylation (AcLDL), were characterized. Aortic epithelial cells were used and a cell culture system which closely resembled the in vivo monolayer was established. Endothelial cell and lipoprotein interactions were examined by incubating the cells with 125 l-labelled lipoproteins under various conditions. The receptor affinity of bovine aortic endothelial cells was higher for AcLDL than that for LDL. Competition studies demonstrated that there were two distinct receptors for LDL and AcLDL on the endothelial cells. AcLDL did not compete with LDL for the LDL receptor, and conversely LDL did not compete with AcLDL for the AcLDL receptor. The receptor activities for LDL and AcLDL were examined as a function of culture age. Whereas the LDL receptor could be regulated, the AcLDL receptor was not as susceptible to regulation. Upon exposing endothelial cells for 72 h to either LDL or AcLDL, it was found that the total amount of cellular cholesterol increased by about 50%. However, the increase of total cholesterol was largely in the form of free cholesterol. This is in contrast to macrophages, where the increase in total cholesterol upon exposure to AcLDL is largely in the form cholesteryl esters

  17. Molecular identification of the first SIFamide receptor

    DEFF Research Database (Denmark)

    Jørgensen, Lars M; Hauser, Frank; Cazzamali, Giuseppe

    2006-01-01

    . Database searches revealed SIFamide receptor orthologues in the genomes from the malaria mosquito Anopheles gambiae, the silkworm Bombyx mori, the red flour beetle Tribolium castaneum, and the honey bee Apis mellifera. An alignment of the five insect SIFamide or SIFamide-like receptors showed, again...

  18. Genetic features of thyroid hormone receptors

    Indian Academy of Sciences (India)

    Abstract. Thyroid hormone receptors (TR) are prototypes of nuclear transcription factors that regulate the expression of target genes. These receptors play an important role in many physiological processes. Moreover, a dysfunction of these proteins is often implicated in several human diseases and malignancies. Here we ...

  19. Emerging functions for neuropeptide Y5 receptors

    NARCIS (Netherlands)

    Bischoff, A.; Michel, M. C.

    1999-01-01

    The Y5 subtype of neuropeptide Y (NPY) receptors has raised considerable interest as a mediator of NPY-stimulated food intake, but with the advent of recent data, this hypothesis has come into question. Moreover, Y5 receptor-selective drugs might not be specific for food intake because additional

  20. Receptor study of psychiatric disorders using PET

    International Nuclear Information System (INIS)

    Suhara, Tetsuya

    1992-01-01

    Recent receptor studies of psychiatric disorders using PET have been focused on the change in the number of D 2 dopamine receptors in the striatum of drug-naive schizophrenic patients. One study confirmed an increase in D 2 receptors, while another study denied it. Although there were some differences in the approaches of the two groups, the reason for the discrepancy is not clear yet. Looking to psychiatric disorders other than schizophrenia, our recent study revealed a possible role of dopamine D 1 receptors in bipolar mood disorders. However, some problems must be resolved for further receptor studies with PET. For example, our recent study shows that desipamine decreases the in vivo binding of dopramine D 1 and D 2 receptors whereas these is no effect on dopamine D 1 and D 2 receptors in vitro. Additionally significant methodological problems lie in the method of evaluation of the non-specific binding and the effect of endogenous neurotransmitters. Moreover, difficulties in the diagnosis of psychiatric disorders and ethical problems in psychiatric research are critical factors in receptor studies with PET in psychiatric disorders. (author)

  1. Thermogenic characterization of ghrelin receptor null mice

    Science.gov (United States)

    Ghrelin is the only known circulating orexigenic hormone that increases food intake and promotes adiposity, and these physiological functions of ghrelin are mediated through its receptor growth hormone secretagogue receptor (GHS-R). Ghrelin/GHS-R signaling plays a crucial role in energy homeostasis....

  2. Enantioselective Transport by a Steroidal Guanidinium Receptor

    NARCIS (Netherlands)

    Baragaña, Beatriz; Blackburn, Adrian G.; Breccia, Perla; Davis, Anthony P.; Mendoza, Javier de; Padrón-Carrillo, José M.; Prados, Pilar; Riedner, Jens; Vries, Johannes G. de

    2002-01-01

    The cationic steroidal receptors 9 and 11 have been synthesized from cholic acid 3. Receptor 9 extracts N-acetyl-α-amino acids from aqueous media into chloroform with enantioselectivities (L:D) of 7-10:1. The lipophilic variant 11 has been employed for the enantioselective transport of

  3. How calcium makes endocytic receptors attractive

    DEFF Research Database (Denmark)

    Andersen, Christian B F; Moestrup, Søren K

    2014-01-01

    'lynchpin' that stabilizes favorable positioning of ligand-attractive receptor residues. In addition to explaining how calcium depletion can cause ligand-receptor dissociation, the new data add further insight into how acidification contributes to dissociation through structural changes that affect...

  4. Immunohistochemical assessment of oestrogen and progesterone receptors

    DEFF Research Database (Denmark)

    Grabau, D A; Thorpe, S M; Knoop, A

    2000-01-01

    Two different methods to determine steroid receptors were analysed with respect to their ability to estimate prognosis in primary breast cancer patients. The immunohistochemical assay (IHA) was compared with the dextran-coated charcoal (DCC) method of receptor determination. A random sample of 281...

  5. P2X receptors in epithelia

    DEFF Research Database (Denmark)

    Leipziger, Jens Georg

    2015-01-01

    P2X receptors are ubiquitously expressed in all epithelial tissues but their functional roles are less well studied. Here we review the current state of knowledge by focusing on functional effects of P2X receptor in secretory and in absorptive tissues. In glandular tissue like the parotid gland b...

  6. Carbamate Insecticides Target Human Melatonin Receptors.

    Science.gov (United States)

    Popovska-Gorevski, Marina; Dubocovich, Margarita L; Rajnarayanan, Rajendram V

    2017-02-20

    Carbaryl (1-naphthyl methylcarbamate) and carbofuran (2,3-dihydro-2,2-dimethyl-7-benzofuranyl methylcarbamate) are among the most toxic insecticides, implicated in a variety of diseases including diabetes and cancer among others. Using an integrated pharmacoinformatics based screening approach, we have identified these insecticides to be structural mimics of the neurohormone melatonin and were able to bind to the putative melatonin binding sites in MT 1 and MT 2 melatonin receptors in silico. Carbaryl and carbofuran then were tested for competition with 2-[ 125 I]-iodomelatonin (300 pM) binding to hMT 1 or hMT 2 receptors stably expressed in CHO cells. Carbaryl and carbofuran showed higher affinity for competition with 2-[ 125 I]-iodomelatonin binding to the hMT 2 compared to the hMT 1 melatonin receptor (33 and 35-fold difference, respectively) as predicted by the molecular modeling. In the presence of GTP (100 μM), which decouples the G-protein linked receptors to modulate signaling, the apparent efficacy of carbaryl and carbofuran for 2-[ 125 I]-iodomelatonin binding for the hMT 1 melatonin receptor was not affected but significantly decreased for the hMT 2 melatonin receptor compatible with receptor antagonist/inverse agonist and agonist efficacy, respectively. Altogether, our data points to a potentially new mechanism through which carbamate insecticides carbaryl and carbofuran could impact human health by altering the homeostatic balance of key regulatory processes by directly binding to melatonin receptors.

  7. NRSAS: Nuclear Receptor Structure Analysis Servers.

    NARCIS (Netherlands)

    Bettler, E.J.M.; Krause, R.; Horn, F.; Vriend, G.

    2003-01-01

    We present a coherent series of servers that can perform a large number of structure analyses on nuclear hormone receptors. These servers are part of the NucleaRDB project, which provides a powerful information system for nuclear hormone receptors. The computations performed by the servers include

  8. Progesterone receptor levels independently predict survival in endometrial adenocarcinoma

    DEFF Research Database (Denmark)

    Nyholm, H C; Christensen, Ib Jarle; Nielsen, Anette Lynge

    1995-01-01

    Estrogen receptor (ER) and progesterone receptor (PR) contents were determined by biochemical (dextran charcoal-coated (DCC) assay) and immunohistochemical (ICA) methods in biopsies from 145 primary endometrial adenocarcinomas and those with eligible receptor measurements were analyzed with respect...

  9. Steroid Hormone Receptor Signals as Prognosticators for Urothelial Tumor

    Directory of Open Access Journals (Sweden)

    Hiroki Ide

    2015-01-01

    Full Text Available There is a substantial amount of preclinical or clinical evidence suggesting that steroid hormone receptor-mediated signals play a critical role in urothelial tumorigenesis and tumor progression. These receptors include androgen receptor, estrogen receptors, glucocorticoid receptor, progesterone receptor, vitamin D receptor, retinoid receptors, peroxisome proliferator-activated receptors, and others including orphan receptors. In particular, studies using urothelial cancer tissue specimens have demonstrated that elevated or reduced expression of these receptors as well as alterations of their upstream or downstream pathways correlates with patient outcomes. This review summarizes and discusses available data suggesting that steroid hormone receptors and related signals serve as biomarkers for urothelial carcinoma and are able to predict tumor recurrence or progression.

  10. Current Research on Opioid Receptor Function

    Science.gov (United States)

    Feng, Yuan; He, Xiaozhou; Yang, Yilin; Chao, Dongman; Lazarus, Lawrence H.; Xia, Ying

    2012-01-01

    The use of opioid analgesics has a long history in clinical settings, although the comprehensive action of opioid receptors is still less understood. Nonetheless, recent studies have generated fresh insights into opioid receptor-mediated functions and their underlying mechanisms. Three major opioid receptors (μ-opioid receptor, MOR; δ-opioid receptor, DOR; and κ-opioid receptor, KOR) have been cloned in many species. Each opioid receptor is functionally sub-classified into several pharmacological subtypes, although, specific gene corresponding each of these receptor subtypes is still unidentified as only a single gene has been isolated for each opioid receptor. In addition to pain modulation and addiction, opioid receptors are widely involved in various physiological and pathophysiological activities, including the regulation of membrane ionic homeostasis, cell proliferation, emotional response, epileptic seizures, immune function, feeding, obesity, respiratory and cardiovascular control as well as some neurodegenerative disorders. In some species, they play an essential role in hibernation. One of the most exciting findings of the past decade is the opioid-receptor, especially DOR, mediated neuroprotection and cardioprotection. The up-regulation of DOR expression and DOR activation increase the neuronal tolerance to hypoxic/ischemic stress. The DOR signal triggers (depending on stress duration and severity) different mechanisms at multiple levels to preserve neuronal survival, including the stabilization of homeostasis and increased pro-survival signaling (e.g., PKC-ERK-Bcl 2) and anti-oxidative capacity. In the heart, PKC and KATP channels are involved in the opioid receptor-mediated cardioprotection. The DOR-mediated neuroprotection and cardioprotection have the potential to significantly alter the clinical pharmacology in terms of prevention and treatment of life-threatening conditions like stroke and myocardial infarction. The main purpose of this article

  11. Computer modeling of Cannabinoid receptor type 1

    Directory of Open Access Journals (Sweden)

    Sapundzhi Fatima

    2018-01-01

    Full Text Available Cannabinoid receptors are important class of receptors as they are involved in various physiological processes such as appetite, pain-sensation, mood, and memory. It is important to design receptor-selective ligands in order to treat a particular disorder. The aim of the present study is to model the structure of cannabinoid receptor CB1 and to perform docking between obtained models and known ligands. Two models of CBR1 were prepared with two different methods (Modeller of Chimera and MOE. They were used for docking with GOLD 5.2. It was established a high correlation between inhibitory constant Ki of CB1 cannabinoid ligands and the ChemScore scoring function of GOLD, which concerns both models. This suggests that the models of the CB1 receptors obtained could be used for docking studies and in further investigation and design of new potential, selective and active cannabinoids with the desired effects.

  12. Complex Pharmacology of Free Fatty Acid Receptors

    DEFF Research Database (Denmark)

    Milligan, Graeme; Shimpukade, Bharat; Ulven, Trond

    2017-01-01

    G protein-coupled receptors (GPCRs) are historically the most successful family of drug targets. In recent times it has become clear that the pharmacology of these receptors is far more complex than previously imagined. Understanding of the pharmacological regulation of GPCRs now extends beyond...... pharmacology have shaped understanding of the complex pharmacology of receptors that recognize and are activated by nonesterified or "free" fatty acids (FFAs). The FFA family of receptors is a recently deorphanized set of GPCRs, the members of which are now receiving substantial interest as novel targets...... for the treatment of metabolic and inflammatory diseases. Further understanding of the complex pharmacology of these receptors will be critical to unlocking their ultimate therapeutic potential....

  13. Molecular pharmacology of human NMDA receptors

    DEFF Research Database (Denmark)

    Hedegaard, Maiken; Hansen, Kasper Bø; Andersen, Karen Toftegaard

    2012-01-01

    current knowledge of the relationship between NMDA receptor structure and function. We summarize studies on the biophysical properties of human NMDA receptors and compare these properties to those of rat orthologs. Finally, we provide a comprehensive pharmacological characterization that allows side......-by-side comparison of agonists, un-competitive antagonists, GluN2B-selective non-competitive antagonists, and GluN2C/D-selective modulators at recombinant human and rat NMDA receptors. The evaluation of biophysical properties and pharmacological probes acting at different sites on the receptor suggest...... that the binding sites and conformational changes leading to channel gating in response to agonist binding are highly conserved between human and rat NMDA receptors. In summary, the results of this study suggest that no major detectable differences exist in the pharmacological and functional properties of human...

  14. Ror receptor tyrosine kinases: orphans no more.

    Science.gov (United States)

    Green, Jennifer L; Kuntz, Steven G; Sternberg, Paul W

    2008-11-01

    Receptor tyrosine kinase-like orphan receptor (Ror) proteins are a conserved family of tyrosine kinase receptors that function in developmental processes including skeletal and neuronal development, cell movement and cell polarity. Although Ror proteins were originally named because the associated ligand and signaling pathway were unknown, recent studies in multiple species have now established that Ror proteins are Wnt receptors. Depending on the cellular context, Ror proteins can either activate or repress transcription of Wnt target genes and can modulate Wnt signaling by sequestering Wnt ligands. New evidence implicates Ror proteins in planar cell polarity, an alternative Wnt pathway. Here, we review the progress made in understanding these mysterious proteins and, in particular, we focus on their function as Wnt receptors.

  15. Androgen insensitivity syndrome: gonadal androgen receptor activity

    International Nuclear Information System (INIS)

    Coulam, C.B.; Graham, M.L.; Spelsberg, T.C.

    1984-01-01

    To determine whether abnormalities of the androgen receptor previously observed in skin fibroblasts from patients with androgen insensitivity syndrome also occur in the gonads of affected individuals, androgen receptor activity in the gonads of a patient with testicular feminization syndrome was investigated. Using conditions for optimal recovery of androgen receptor from human testes established by previous studies, we detected the presence of a high-affinity (dissociation constant . 3.2 X 10(-10) mol/L), low-capacity (4.2 X 10(-12) mol/mg DNA), androgen-binding protein when tritium-labeled R1881 was incubated at 4 degrees C with nuclear extracts from the gonads of control patients or from a patient with testicular feminization syndrome but not when incubated at 37 degrees C. Thus this patient has an androgen receptor with a temperature lability similar to that of receptors from normal persons

  16. Kinetic Profile of Neuropeptide-Receptor Interactions.

    Science.gov (United States)

    Nederpelt, Indira; Bunnik, Julia; IJzerman, Adriaan P; Heitman, Laura H

    2016-12-01

    Currently, drug discovery focusses only on quantifying pharmacological parameters, sometimes including binding kinetics, of drug candidates. For a complete understanding of a drug's desired binding kinetics, the kinetics of both the target and its endogenous ligands should be considered. This is because the release and binding kinetics of endogenous ligands in addition to receptor internalization rates are significant contributors to drug-target interactions. Here, we discuss the kinetic profile of three neuropeptides and their receptors; gonadotropin-releasing hormone receptor (GnRHR), neuropeptide Y receptors, and corticotropin-releasing factor receptor 1 (CRF 1 R). These three examples provide new insights into the importance of kinetic profiles which could improve the understanding of desired drug-target binding kinetics and advance drug discovery for various neurological and psychiatric illnesses. Copyright © 2016 Elsevier Ltd. All rights reserved.

  17. Mutations in G protein-coupled receptors that impact receptor trafficking and reproductive function.

    Science.gov (United States)

    Ulloa-Aguirre, Alfredo; Zariñán, Teresa; Dias, James A; Conn, P Michael

    2014-01-25

    G protein coupled receptors (GPCRs) are a large superfamily of integral cell surface plasma membrane proteins that play key roles in transducing extracellular signals, including sensory stimuli, hormones, neurotransmitters, or paracrine factors into the intracellular environment through the activation of one or more heterotrimeric G proteins. Structural alterations provoked by mutations or variations in the genes coding for GPCRs may lead to misfolding, altered plasma membrane expression of the receptor protein and frequently to disease. A number of GPCRs regulate reproductive function at different levels; these receptors include the gonadotropin-releasing hormone receptor (GnRHR) and the gonadotropin receptors (follicle-stimulating hormone receptor and luteinizing hormone receptor), which regulate the function of the pituitary-gonadal axis. Loss-of-function mutations in these receptors may lead to hypogonadotropic or hypergonadotropic hypogonadism, which encompass a broad spectrum of clinical phenotypes. In this review we describe mutations that provoke misfolding and failure of these receptors to traffick from the endoplasmic reticulum to the plasma membrane. We also discuss some aspects related to the therapeutic potential of some target-specific drugs that selectively bind to and rescue function of misfolded mutant GnRHR and gonadotropin receptors, and that represent potentially valuable strategies to treat diseases caused by inactivating mutations of these receptors. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  18. Real-Time G-Protein-Coupled Receptor Imaging to Understand and Quantify Receptor Dynamics

    Directory of Open Access Journals (Sweden)

    María S. Aymerich

    2011-01-01

    Full Text Available Understanding the trafficking of G-protein-coupled receptors (GPCRs and their regulation by agonists and antagonists is fundamental to develop more effective drugs. Optical methods using fluorescent-tagged receptors and spinning disk confocal microscopy are useful tools to investigate membrane receptor dynamics in living cells. The aim of this study was to develop a method to characterize receptor dynamics using this system which offers the advantage of very fast image acquisition with minimal cell perturbation. However, in short-term assays photobleaching was still a problem. Thus, we developed a procedure to perform a photobleaching-corrected image analysis. A study of short-term dynamics of the long isoform of the dopamine type 2 receptor revealed an agonist-induced increase in the mobile fraction of receptors with a rate of movement of 0.08 μm/s For long-term assays, the ratio between the relative fluorescence intensity at the cell surface versus that in the intracellular compartment indicated that receptor internalization only occurred in cells co-expressing G protein-coupled receptor kinase 2. These results indicate that the lateral movement of receptors and receptor internalization are not directly coupled. Thus, we believe that live imaging of GPCRs using spinning disk confocal image analysis constitutes a powerful tool to study of receptor dynamics.

  19. Receptor oligomerization in family B1 of G-protein-coupled receptors

    DEFF Research Database (Denmark)

    Roed, Sarah Norklit; Ørgaard, Anne; Jørgensen, Rasmus

    2012-01-01

    , investigation of family B1 receptor oligomerization and especially its pharmacological importance is still at an early stage. Even though GPCR oligomerization is a well-established phenomenon, there is a need for more investigations providing a direct link between these interactions and receptor functionality......The superfamily of the seven transmembrane G-protein-coupled receptors (7TM/GPCRs) is the largest family of membrane-associated receptors. GPCRs are involved in the pathophysiology of numerous human diseases, and they constitute an estimated 30-40% of all drug targets. During the last two decades......, GPCR oligomerization has been extensively studied using methods like bioluminescence resonance energy transfer (BRET) and today, receptor-receptor interactions within the GPCR superfamily is a well-established phenomenon. Evidence of the impact of GPCR oligomerization on, e.g., ligand binding, receptor...

  20. Enhanced sensitivity of muscarinic cholinergic receptor associated with dopaminergic receptor subsensitivity after chronic antidepressant treatment

    International Nuclear Information System (INIS)

    Koide, T.; Matsushita, H.

    1981-01-01

    The chronic effects of antidepressant treatment on striatal dopaminergic (DA) and muscarinic cholinergic (mACh) receptors of the rat brain have been examined comparatively in this study using 3 H-spiroperidol ( 3 H-SPD) and 3 H-quinuclidinyl benzilate ( 3 H-QNB) as the respective radioactive ligands. Imipramine and desipramine were used as prototype antidepressants. Although a single administration of imipramine or desipramine did not affect each receptor sensitivity, chronic treatment with each drug caused a supersensitivity of mACh receptor subsequent to DA receptor subsensitivity. Furthermore, it has been suggested that anti-mACh properties of imipramine or desipramine may not necessarily be related to the manifestation of mACh receptor supersensitivity and that sustained DA receptor subsensitivity may play some role in the alterations of mACh receptor sensitivity

  1. Multiple autophosphorylation sites of the epidermal growth factor receptor are essential for receptor kinase activity and internalization. Contrasting significance of tyrosine 992 in the native and truncated receptors

    DEFF Research Database (Denmark)

    Sorkin, A; Helin, K; Waters, C M

    1992-01-01

    for cells expressing kinase-negative receptor (A721). Moreover, tyrosine kinase activity of the Dc-123F receptor toward phospholipase C-gamma 1, compared to wild-type receptor, was reduced by 90%. Taken together, these results show that EGF receptor lacking five autophosphorylation sites functions similar...

  2. Emerging GLP-1 receptor agonists

    DEFF Research Database (Denmark)

    Lund, Asger; Knop, Filip K; Vilsbøll, Tina

    2011-01-01

    Introduction: Recently, glucagon-like peptide-1 receptor (GLP-1R) agonists have become available for the treatment of type 2 diabetes. These agents exploit the physiological effects of GLP-1, which is able to address several of the pathophysiological features of type 2 diabetes. GLP-1R agonists...... presently available are administered once or twice daily, but several once-weekly GLP-1R agonists are in late clinical development. Areas covered: The present review aims to give an overview of the clinical data on the currently available GLP-1R agonists used for treatment of type 2 diabetes, exenatide...... and liraglutide, as well as the emerging GLP-1R agonists including the long-acting compounds. Expert opinion: An emerging therapeutic trend toward initial or early combination therapy with metformin- and incretin-based therapy is anticipated for patients with type 2 diabetes. GLP-1-based therapy has so far proven...

  3. Ketamine: NMDA Receptors and Beyond.

    Science.gov (United States)

    Zorumski, Charles F; Izumi, Yukitoshi; Mennerick, Steven

    2016-11-02

    Human studies examining the effects of the dissociative anesthetic ketamine as a model for psychosis and as a rapidly acting antidepressant have spurred great interest in understanding ketamine's actions at molecular, cellular, and network levels. Although ketamine has unequivocal uncompetitive inhibitory effects on N-methyl-d-aspartate receptors (NMDARs) and may preferentially alter the function of NMDARs on interneurons, recent work has questioned whether block of NMDARs is critical for its mood enhancing actions. In this viewpoint, we examine the evolving literature on ketamine supporting NMDARs as important triggers for certain psychiatric effects and the possibility that the antidepressant trigger is unrelated to NMDARs. The rapidly evolving story of ketamine offers great hope for untangling and treating the biology of both depressive and psychotic illnesses. Copyright © 2016 the authors 0270-6474/16/3611158-07$15.00/0.

  4. THE NATURE OF ACETYLCHOLINE RECEPTOR

    Directory of Open Access Journals (Sweden)

    M.E. TASHAYOD

    1983-05-01

    Full Text Available The present work with consideratlon to the autoradiographic pictures, suggests that cholinergic receptors are located at the gate of a channel originating from synaptic cleft coming to lie within the muscle fibre. AChE molecules stand at the gate of this channel,controlling the entrance of different cholinergic agents. It was report- ••• ed previously that dtc molecules s t.abD ;:.2e the AChE rnolecules and will obstruct the gate. This blocks the acess of ionic flux within the channel thus producing a non-depolarizing neuromuscular paralysis.The presented experiments imply that depolarizing agent will bring a considerable change in conformation of AChE mole cule and this causes the opening of the gate allowing ioni flux and depolarization .In case of ACh this process is repeated in a fraction of milli second, due to rapid regeneration of AChE while in case of suxamethonium and neostigmine(given in high dose, the regeneration of AChE takes much longer time thus will produce a depolarizing blockade. In this hypothepis the main responsa~ility of AChE"nis confined to identification of cholinergic agents and Cooperation in their function so,it can be accepted as Cholinergic receptor. In regard to clinic, this work suggests that only the use of minimum effective dose of neostigmine is advisable, in reversing curarisation. In contrast to general belief , the dose of neostigmine should be s elec t ed in relation to r eceptor dtc occupation and not depending on pati ent 's weight . As it was demonstrated , the early use"nof high dose o f neostigmine may a lso potent i a te curar i s a tion

  5. G-protein Receptor Kinase 5 Regulates the Cannabinoid Receptor 2-induced Up-regulation of Serotonin 2A Receptors*

    Science.gov (United States)

    Franklin, Jade M.; Carrasco, Gonzalo A.

    2013-01-01

    We have recently reported that cannabinoid agonists can up-regulate and enhance the activity of serotonin 2A (5-HT2A) receptors in the prefrontal cortex (PFCx). Increased expression and activity of cortical 5-HT2A receptors has been associated with neuropsychiatric disorders, such as anxiety and schizophrenia. Here we report that repeated CP55940 exposure selectively up-regulates GRK5 proteins in rat PFCx and in a neuronal cell culture model. We sought to examine the mechanism underlying the regulation of GRK5 and to identify the role of GRK5 in the cannabinoid agonist-induced up-regulation and enhanced activity of 5-HT2A receptors. Interestingly, we found that cannabinoid agonist-induced up-regulation of GRK5 involves CB2 receptors, β-arrestin 2, and ERK1/2 signaling because treatment with CB2 shRNA lentiviral particles, β-arrestin 2 shRNA lentiviral particles, or ERK1/2 inhibitor prevented the cannabinoid agonist-induced up-regulation of GRK5. Most importantly, we found that GRK5 shRNA lentiviral particle treatment prevented the cannabinoid agonist-induced up-regulation and enhanced 5-HT2A receptor-mediated calcium release. Repeated cannabinoid exposure was also associated with enhanced phosphorylation of CB2 receptors and increased interaction between β-arrestin 2 and ERK1/2. These latter phenomena were also significantly inhibited by GRK5 shRNA lentiviral treatment. Our results suggest that sustained activation of CB2 receptors, which up-regulates 5-HT2A receptor signaling, enhances GRK5 expression; the phosphorylation of CB2 receptors; and the β-arrestin 2/ERK interactions. These data could provide a rationale for some of the adverse effects associated with repeated cannabinoid agonist exposure. PMID:23592773

  6. Renal tubular vasopressin receptors downregulated by dehydration

    International Nuclear Information System (INIS)

    Steiner, M.; Phillips, M.I.

    1988-01-01

    Receptors for arginine vasopressin (AVP) were characterized in tubular epithelial basolateral membranes (BL membranes) prepared from the kidneys of male Spraque-Dawley rats. Association of [ 3 H]AVP was rapid, reversible, and specific. Saturation studies revealed a single class of saturable binding sites with a maximal binding (B max ) of 184 ± 15 fmol/mg protein. The V 2 receptor antagonist was more than 3,700 times as effective in displacing [ 3 H]AVP than was the V 1 antagonist. To investigate the physiological regulation of vasopressin receptors, the effects of elevated levels of circulating AVP on receptor characteristics were studied. Seventy-two-hour water deprivation significantly elevated plasma osmolality and caused an 11.5-fold increase in plasma [AVP]. Scatchard analysis revealed a 38% decreased in the number of AVP receptors on the BL membranes from dehydrated animals. The high-affinity binding sites on the BL membranes fit the pharmacological profile for adenylate cyclase-linked vasopressin receptors (V 2 ), which mediate the antidiuretic action of the hormone. The authors conclude that physiologically elevated levels of AVP can downregulate vasopressin receptors in the kidney

  7. Muscarinic Receptor Signaling in Colon Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Rosenvinge, Erik C. von, E-mail: evonrose@medicine.umaryland.edu; Raufman, Jean-Pierre [University of Maryland School of Medicine, Division of Gastroenterology & Hepatology, 22 S. Greene Street, N3W62, Baltimore, MD 21201 (United States); Department of Veterans Affairs, VA Maryland Health Care System, 10 North Greene Street, Baltimore, MD 21201 (United States)

    2011-03-02

    According to the adenoma-carcinoma sequence, colon cancer results from accumulating somatic gene mutations; environmental growth factors accelerate and augment this process. For example, diets rich in meat and fat increase fecal bile acids and colon cancer risk. In rodent cancer models, increased fecal bile acids promote colon dysplasia. Conversely, in rodents and in persons with inflammatory bowel disease, low-dose ursodeoxycholic acid treatment alters fecal bile acid composition and attenuates colon neoplasia. In the course of elucidating the mechanism underlying these actions, we discovered that bile acids interact functionally with intestinal muscarinic receptors. The present communication reviews muscarinic receptor expression in normal and neoplastic colon epithelium, the role of autocrine signaling following synthesis and release of acetylcholine from colon cancer cells, post-muscarinic receptor signaling including the role of transactivation of epidermal growth factor receptors and activation of the ERK and PI3K/AKT signaling pathways, the structural biology and metabolism of bile acids and evidence for functional interaction of bile acids with muscarinic receptors on human colon cancer cells. In murine colon cancer models, deficiency of subtype 3 muscarinic receptors attenuates intestinal neoplasia; a proof-of-concept supporting muscarinic receptor signaling as a therapeutic target for colon cancer.

  8. Action mechanisms of Liver X Receptors

    International Nuclear Information System (INIS)

    Gabbi, Chiara; Warner, Margaret; Gustafsson, Jan-Åke

    2014-01-01

    Highlights: • LXRα and LXRβ are ligand-activated nuclear receptors. • They share oxysterol ligands and the same heterodimerization partner, RXR. • LXRs regulate lipid and glucose metabolism, CNS and immune functions, and water transport. - Abstract: The two Liver X Receptors, LXRα and LXRβ, are nuclear receptors belonging to the superfamily of ligand-activated transcription factors. They share more than 78% homology in amino acid sequence, a common profile of oxysterol ligands and the same heterodimerization partner, Retinoid X Receptor. LXRs play crucial roles in several metabolic pathways: lipid metabolism, in particular in preventing cellular cholesterol accumulation; glucose homeostasis; inflammation; central nervous system functions and water transport. As with all nuclear receptors, the transcriptional activity of LXR is the result of an orchestration of numerous cellular factors including ligand bioavailability, presence of corepressors and coactivators and cellular context i.e., what other pathways are activated in the cell at the time the receptor recognizes its ligand. In this mini-review we summarize the factors regulating the transcriptional activity and the mechanisms of action of these two receptors

  9. Action mechanisms of Liver X Receptors

    Energy Technology Data Exchange (ETDEWEB)

    Gabbi, Chiara; Warner, Margaret [Center for Nuclear Receptors and Cell Signaling, University of Houston, 3056 Cullen Blv, 77204 Houston, Texas (United States); Gustafsson, Jan-Åke, E-mail: jgustafs@central.uh.edu [Center for Nuclear Receptors and Cell Signaling, University of Houston, 3056 Cullen Blv, 77204 Houston, Texas (United States); Department of Biosciences and Nutrition, Karolinska Institutet, Novum S-141 86 (Sweden)

    2014-04-11

    Highlights: • LXRα and LXRβ are ligand-activated nuclear receptors. • They share oxysterol ligands and the same heterodimerization partner, RXR. • LXRs regulate lipid and glucose metabolism, CNS and immune functions, and water transport. - Abstract: The two Liver X Receptors, LXRα and LXRβ, are nuclear receptors belonging to the superfamily of ligand-activated transcription factors. They share more than 78% homology in amino acid sequence, a common profile of oxysterol ligands and the same heterodimerization partner, Retinoid X Receptor. LXRs play crucial roles in several metabolic pathways: lipid metabolism, in particular in preventing cellular cholesterol accumulation; glucose homeostasis; inflammation; central nervous system functions and water transport. As with all nuclear receptors, the transcriptional activity of LXR is the result of an orchestration of numerous cellular factors including ligand bioavailability, presence of corepressors and coactivators and cellular context i.e., what other pathways are activated in the cell at the time the receptor recognizes its ligand. In this mini-review we summarize the factors regulating the transcriptional activity and the mechanisms of action of these two receptors.

  10. Tachykinins and tachykinin receptors in bone.

    Science.gov (United States)

    Goto, Tetsuya; Tanaka, Teruo

    2002-07-15

    Tachykinins are neuropeptides that are widely distributed in the body and function as neurotransmitters and neuromodulators. Five tachykinin subtypes: substance P (SP), neurokinin A, neurokinin B, neuropeptide K, and neuropeptide gamma; and three receptor subtypes: neurokinin-1, -2, and -3 receptors, have been identified. SP was the first peptide of the tachykinin family to be identified. It is considered to be an important neuropeptide, and to function in the nervous system and intestine. However, recent advances in the analysis of SP receptors, particularly neurokinin-1 receptors (NK(1)-Rs) that have high affinity for SP, have demonstrated that NK(1)-Rs are distributed not only in neurons and immune cells, but also in other peripheral cells, including bone cells. This article reviews the current understanding of the distribution of SP and other tachykinins in bone, and the function of tachykinins, through neurokinin receptors. The distribution of tachykinin-immunoreactive axons and neurokinin receptors suggests that tachykinins may directly modulate bone metabolism through neurokinin receptors. Copyright 2002 Wiley-Liss, Inc.

  11. Pharmacological analysis of calcium antagonist receptors

    International Nuclear Information System (INIS)

    Reynolds, I.J.

    1987-01-01

    This work focuses on two aspects of the action of calcium antagonist drugs, namely, the interaction of drugs with receptors for verapamil-like calcium antagonists, and the interactions of drugs with voltage-sensitive calcium fluxes in rat brain synaptosomes. From binding studies I have found that the ligand of choice for labeling the verapamil receptor is (-)[ 3 H]desmethoxy-verapamil. This drug labels potently, reversibly and stereoselectively two receptors in membranes prepared from rat brain and rabbit skeletal muscle tissues. In equilibrium studies dihydropyridine calcium antagonists interact in a non-competitive fashion, while many non-DHPs are apparently competitive. In-depth kinetic studies in skeletal muscle membranes indicate that the two receptors are linked in a negative heterotropic fashion, and that low-affinity binding of (-) [ 3 H]desmethoxy-verapamil may be to the diltiazem receptor. However, these studies were not able to distinguish between the hypothesis that diltiazem binds to spatially separate, allosterically coupled receptors, and the hypothesis that diltiazem binds to a subsite of the verapamil receptor

  12. Psychopharmacology of 5-HT1A receptors

    International Nuclear Information System (INIS)

    Cowen, Philip J.

    2000-01-01

    Serotonin 1A (5-HT 1A ) receptors are located on both 5-HT cell bodies where they act as inhibitory autoreceptors and at postsynaptic sites where they mediate the effects of 5-HT released from nerve terminals. The sensitivity of 5-HT 1A receptors in humans can be measured using the technique of pharmacological challenge. For example, acute administration of a selective 5-HT 1A receptor agonist, such as ipsapirone, decreases body temperature and increases plasma cortisol through activation of pre- and postsynaptic 5-HT 1A receptors, respectively. Use of this technique has demonstrated that unmedicated patients with major depression have decreased sensitivity of both pre- and postsynaptic 5-HT 1A receptors. Treatment with selective serotonin reuptake inhibitors further down-regulates 5-HT 1A receptor activity. Due to the hypotheses linking decreased sensitivity of 5-HT 1A autoreceptors with the onset of antidepressant activity, there is current interest in the therapeutic efficacy of combined treatment with selective serotonin reuptake inhibitors and 5-HT 1A receptor antagonists

  13. Receptor mapping in psychiatric patients with SPECT

    International Nuclear Information System (INIS)

    Schlegel, S.

    1997-01-01

    This paper summarizes some data of our studies with the single-photon-emission-computerized tomography (SPECT), focussing on the dopamine-D2- and the benzodiazepine receptor mapping. Benzodiazepine receptors: Central benzodiazepine receptors (BZr) can be visualized with iomazenil which is an analogue of the benzodiazepine antagonist flumazenil, labeled with 123-iodine. Since the involvement of the BZr system is discussed in the pathogenesis of anxiety and depression, patients with these disorders were investigated. A third study investigated the BZr-occupancy during benzodiazepine treatment (lorazepam). Results: (a) Patients with panic disorders had lower iomazenil uptake values compared to epileptic patients. (b) Depressed patients showed a positive correlation between severity of illness and frontal uptake. (c) BZr occupancy during lorazepam treatment was measurable, but not associated with lorazepam plasma levels. Dopamine-D2-receptors: With 123-I-iodobenzamide (IBZM), and iodine-labeled dopamine receptor ligand, the D2 receptor density can be measured by a semiquantitative approach (striatum/frontal cortex=ST/FC). Therefore, we investigated the D2-receptor occupancy during treatment with typical and atypical neuroleptics in relationship to dosages (normalized with different formulas of chlorpromazine equivalents), side effects, and prolactin plasma levels. Results: Dependent on the selected formula for chlorpromazine equivalents, the ST/FC ratio was correlated with dosages. Side effects and prolactin plasma levels showed a negative association with lower ST/FC ratios. (orig.) [de

  14. Muscarinic Receptor Signaling in Colon Cancer

    International Nuclear Information System (INIS)

    Rosenvinge, Erik C. von; Raufman, Jean-Pierre

    2011-01-01

    According to the adenoma-carcinoma sequence, colon cancer results from accumulating somatic gene mutations; environmental growth factors accelerate and augment this process. For example, diets rich in meat and fat increase fecal bile acids and colon cancer risk. In rodent cancer models, increased fecal bile acids promote colon dysplasia. Conversely, in rodents and in persons with inflammatory bowel disease, low-dose ursodeoxycholic acid treatment alters fecal bile acid composition and attenuates colon neoplasia. In the course of elucidating the mechanism underlying these actions, we discovered that bile acids interact functionally with intestinal muscarinic receptors. The present communication reviews muscarinic receptor expression in normal and neoplastic colon epithelium, the role of autocrine signaling following synthesis and release of acetylcholine from colon cancer cells, post-muscarinic receptor signaling including the role of transactivation of epidermal growth factor receptors and activation of the ERK and PI3K/AKT signaling pathways, the structural biology and metabolism of bile acids and evidence for functional interaction of bile acids with muscarinic receptors on human colon cancer cells. In murine colon cancer models, deficiency of subtype 3 muscarinic receptors attenuates intestinal neoplasia; a proof-of-concept supporting muscarinic receptor signaling as a therapeutic target for colon cancer

  15. Muscarinic Receptor Signaling in Colon Cancer

    Directory of Open Access Journals (Sweden)

    Jean-Pierre Raufman

    2011-03-01

    Full Text Available According to the adenoma-carcinoma sequence, colon cancer results from accumulating somatic gene mutations; environmental growth factors accelerate and augment this process. For example, diets rich in meat and fat increase fecal bile acids and colon cancer risk. In rodent cancer models, increased fecal bile acids promote colon dysplasia. Conversely, in rodents and in persons with inflammatory bowel disease, low-dose ursodeoxycholic acid treatment alters fecal bile acid composition and attenuates colon neoplasia. In the course of elucidating the mechanism underlying these actions, we discovered that bile acids interact functionally with intestinal muscarinic receptors. The present communication reviews muscarinic receptor expression in normal and neoplastic colon epithelium, the role of autocrine signaling following synthesis and release of acetylcholine from colon cancer cells, post-muscarinic receptor signaling including the role of transactivation of epidermal growth factor receptors and activation of the ERK and PI3K/AKT signaling pathways, the structural biology and metabolism of bile acids and evidence for functional interaction of bile acids with muscarinic receptors on human colon cancer cells. In murine colon cancer models, deficiency of subtype 3 muscarinic receptors attenuates intestinal neoplasia; a proof-of-concept supporting muscarinic receptor signaling as a therapeutic target for colon cancer.

  16. Andrographolide regulates epidermal growth factor receptor and transferrin receptor trafficking in epidermoid carcinoma (A-431) cells

    Science.gov (United States)

    Tan, Y; Chiow, KH; Huang, D; Wong, SH

    2010-01-01

    Background and purpose: Andrographolide is the active component of Andrographis paniculata, a plant used in both Indian and Chinese traditional medicine, and it has been demonstrated to induce apoptosis in different cancer cell lines. However, not much is known about how it may affect the key receptors implicated in cancer. Knowledge of how andrographolide affects receptor trafficking will allow us to better understand new mechanisms by which andrographolide may cause death in cancer cells. Experimental approach: We utilized the well-characterized epidermal growth factor receptor (EGFR) and transferrin receptor (TfR) expressed in epidermoid carcinoma (A-431) cells as a model to study the effect of andrographolide on receptor trafficking. Receptor distribution, the total number of receptors and surface receptors were analysed by immunofluorescence, Western blot as well as flow-cytometry respectively. Key results: Andrographolide treatment inhibited cell growth, down-regulated EGFRs on the cell surface and affected the degradation of EGFRs and TfRs. The EGFR was internalized into the cell at an increased rate, and accumulated in a compartment that co-localizes with the lysosomal-associated membrane protein in the late endosomes. Conclusion and implications: This study sheds light on how andrographolide may affect receptor trafficking by inhibiting receptor movement from the late endosomes to lysosomes. The down-regulation of EGFR from the cell surface also indicates a new mechanism by which andrographolide may induce cancer cell death. PMID:20233216

  17. Serotonin 5-HT4 receptors and forebrain cholinergic system: receptor expression in identified cell populations.

    Science.gov (United States)

    Peñas-Cazorla, Raúl; Vilaró, M Teresa

    2015-11-01

    Activation of serotonin 5-HT4 receptors has pro-cognitive effects on memory performance. The proposed underlying neurochemical mechanism is the enhancement of acetylcholine release in frontal cortex and hippocampus elicited by 5-HT4 agonists. Although 5-HT4 receptors are present in brain areas related to cognition, e.g., hippocampus and cortex, the cellular localization of the receptors that might modulate acetylcholine release is unknown at present. We have analyzed, using dual label in situ hybridization, the cellular localization of 5-HT4 receptor mRNA in identified neuronal populations of the rat basal forebrain, which is the source of the cholinergic innervation to cortex and hippocampus. 5-HT4 receptor mRNA was visualized with isotopically labeled oligonucleotide probes, whereas cholinergic, glutamatergic, GABAergic and parvalbumin-synthesizing neurons were identified with digoxigenin-labeled oligonucleotide probes. 5-HT4 receptor mRNA was not detected in the basal forebrain cholinergic cell population. In contrast, basal forebrain GABAergic, parvalbumin synthesizing, and glutamatergic cells contained 5-HT4 receptor mRNA. Hippocampal and cortical glutamatergic neurons also express this receptor. These results indicate that 5-HT4 receptors are not synthesized by cholinergic cells, and thus would be absent from cholinergic terminals. In contrast, several non-cholinergic cell populations within the basal forebrain and its target hippocampal and cortical areas express these receptors and are thus likely to mediate the enhancement of acetylcholine release elicited by 5-HT4 agonists.

  18. Andrographolide regulates epidermal growth factor receptor and transferrin receptor trafficking in epidermoid carcinoma (A-431) cells.

    Science.gov (United States)

    Tan, Y; Chiow, K H; Huang, D; Wong, S H

    2010-04-01

    Andrographolide is the active component of Andrographis paniculata, a plant used in both Indian and Chinese traditional medicine, and it has been demonstrated to induce apoptosis in different cancer cell lines. However, not much is known about how it may affect the key receptors implicated in cancer. Knowledge of how andrographolide affects receptor trafficking will allow us to better understand new mechanisms by which andrographolide may cause death in cancer cells. We utilized the well-characterized epidermal growth factor receptor (EGFR) and transferrin receptor (TfR) expressed in epidermoid carcinoma (A-431) cells as a model to study the effect of andrographolide on receptor trafficking. Receptor distribution, the total number of receptors and surface receptors were analysed by immunofluorescence, Western blot as well as flow-cytometry respectively. Andrographolide treatment inhibited cell growth, down-regulated EGFRs on the cell surface and affected the degradation of EGFRs and TfRs. The EGFR was internalized into the cell at an increased rate, and accumulated in a compartment that co-localizes with the lysosomal-associated membrane protein in the late endosomes. This study sheds light on how andrographolide may affect receptor trafficking by inhibiting receptor movement from the late endosomes to lysosomes. The down-regulation of EGFR from the cell surface also indicates a new mechanism by which andrographolide may induce cancer cell death.

  19. Pharmacological and autoradiographic characterization of sigma receptors

    International Nuclear Information System (INIS)

    Largent, B.L.

    1986-01-01

    The existence of three types of opioid receptors - μ, kappa, and sigma - was postulated to explain the effects of different opioids in the chronic spinal dog. Sigma receptors, named for the prototypic agonist SKF 10,047 (N-allylnormetazocine), were suggested to mediate the psychotomimetic-like effects of SKF 10,047 in the dog. 3-(3-Hydroxyphenyl)-N-(1-propyl)piperidine (3-PPP) has been proposed as a selective dopamine autoreceptor agonist. However, the drug specificity of (+)[ 3 H]3-PPP binding in brain is identical to that of sigma receptor binding sites which may mediate psychotomimetic effects of some opioids. Pharmacological and autoradiographic analyses reveal that (+)[ 3 H]SKF 10,047, the prototypic sigma agonist, labels two sites in brain. The drug specificity of the high affinity site for (+)[ 3 H]SKF 10,047 resembles that of putative sigma receptors labeled with (+)[ 3 H]3-PPP, being potently inhibited by (+)3-PPP, haloperidol, and (+/-)pentazocine, and demonstrating stereoselectivity for the (+) isomer of SKF 10,047. Autoradiographic localizations of high affinity (+)[ 3 H]SKF 10,047 binding sites closely resemble those of (+)[ 3 H]3-PPP labeled sites with high levels of binding in the hippocampal pyramidal cell layer, hypothalamus, and pontine and cranial nerve nuclei. Thus, putative sigma receptors and PCP receptors represent distinct receptor populations in brain. This proposal is supported by the presence of sigma binding sites - and absence of PCP receptors - on NCB-20 cell membranes, a hybrid neurotumor cell line that provides a model system for the physiological and biochemical study of sigma receptors

  20. Role of adenosine receptors in caffeine tolerance

    International Nuclear Information System (INIS)

    Holtzman, S.G.; Mante, S.; Minneman, K.P.

    1991-01-01

    Caffeine is a competitive antagonist at adenosine receptors. Receptor up-regulation during chronic drug treatment has been proposed to be the mechanism of tolerance to the behavioral stimulant effects of caffeine. This study reassessed the role of adenosine receptors in caffeine tolerance. Separate groups of rats were given scheduled access to drinking bottles containing plain tap water or a 0.1% solution of caffeine. Daily drug intake averaged 60-75 mg/kg and resulted in complete tolerance to caffeine-induced stimulation of locomotor activity, which could not be surmounted by increasing the dose of caffeine. 5'-N-ethylcarboxamidoadenosine (0.001-1.0 mg/kg) dose dependently decreased the locomotor activity of caffeine-tolerant rats and their water-treated controls but was 8-fold more potent in the latter group. Caffeine (1.0-10 mg/kg) injected concurrently with 5-N-ethylcarboxamidoadenosine antagonized the decreases in locomotor activity comparably in both groups. Apparent pA2 values for tolerant and control rats also were comparable: 5.05 and 5.11. Thus, the adenosine-antagonist activity of caffeine was undiminished in tolerant rats. The effects of chronic caffeine administration on parameters of adenosine receptor binding and function were measured in cerebral cortex. There were no differences between brain tissue from control and caffeine-treated rats in number and affinity of adenosine binding sites or in receptor-mediated increases (A2 adenosine receptor) and decreases (A1 adenosine receptor) in cAMP accumulation. These results are consistent with theoretical arguments that changes in receptor density should not affect the potency of a competitive antagonist. Experimental evidence and theoretical considerations indicate that up-regulation of adenosine receptors is not the mechanism of tolerance to caffeine-induced stimulation of locomotor activity

  1. Identification of the haemoglobin scavenger receptor

    DEFF Research Database (Denmark)

    Kristiansen, M; Graversen, Jonas Heilskov; Jacobsen, C

    2001-01-01

    haptoglobin, which is depleted from plasma during elevated haemolysis. Here we report the identification of the acute phase-regulated and signal-inducing macrophage protein, CD163, as a receptor that scavenges haemoglobin by mediating endocytosis of haptoglobin-haemoglobin complexes. CD163 binds only...... haptoglobin and haemoglobin in complex, which indicates the exposure of a receptor-binding neoepitope. The receptor-ligand interaction is Ca2+-dependent and of high affinity. Complexes of haemoglobin and multimeric haptoglobin (the 2-2 phenotype) exhibit higher functional affinity for CD 163 than do complexes...

  2. Transitional cell carcinoma express vitamin D receptors

    DEFF Research Database (Denmark)

    Hermann, G G; Andersen, C B

    1997-01-01

    Recently, vitamin D analogues have shown antineoplastic effect in several diseases. Vitamin D analogues exert its effect by interacting with the vitamin D receptor (VDR). Studies of VDR in transitional cell carcinoma (TCC) have not been reported. The purpose of the present study was therefore.......05). Similarly, also tumor grade appeared to be related to the number of cells expressing the receptor. Normal urothlium also expressed VDR but only with low intensity. Our study shows that TCC cells possess the VDR receptor which may make them capable to respond to stimulation with vitamin D, but functional...

  3. [Progress of pattern recognition receptors of molluscs].

    Science.gov (United States)

    Gao, Qian; Zhao, Qin-ping; Ma, Xiao-xue; Dong, Hui-fen

    2015-08-01

    Molluscs have established complete innate immunity to defense against pathogens. The pattern recognition receptors (PRRs) are the sensory receptors of molluscs to resist outside invaders, as the first reactor to initiate the innate immune response. Some PRRs have been identified in several molluscs, including Toll-like receptors (TLRs) , C-type lectins, galectins, lipopolysaccharide-β-1,3-glucan binding protein (LGBP), Clq domain-containing protein (ClqDC), and peptidoglycan recognition protein (PGRP). PRRs have various biological activities and play important roles in the defense system of molluscs. This paper reviews the research progress of PRRs in molluscs.

  4. Synergistic action of cisplatin and echistatin in MDA-MB-231 breast cancer cells.

    Science.gov (United States)

    Czarnomysy, Robert; Surażyński, Arkadiusz; Popławska, Bożena; Rysiak, Edyta; Pawłowska, Natalia; Czajkowska, Anna; Bielawski, Krzysztof; Bielawska, Anna

    2017-03-01

    The aim of our study was to determine whether the use of cisplatin in the presence echistatin in MDA-MB-231 breast cancer cells leads to a reduction of toxic effects associated with the use of cisplatin. The expression of β 1 -integrin and insulin-like growth factor 1 receptor (IGF-IR), signaling pathway protein expression: protein kinase B (AKT), mitogen-activated protein kinases (ERK1/ERK2), nuclear factor kappa B (NFκB), and caspase-3 and -9 activity was measured after 24 h of incubation with tested compounds to explain detailed molecular mechanism of induction of apoptosis. The viability of MDA-MB-231 breast cancer cells was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Annexin V-FITC/propidium iodide staining assay was performed to detect the induction of apoptosis. Inhibition DNA biosynthesis was determined by [ 3 H]thymidine incorporation into DNA. The expression of of β 1 -integrin, IGF-IR, AKT, ERK1/ERK2, NFκB, caspase-3 and -9 was evaluated using Western blot. The results suggest that treatment of MDA-MB-231 breast cancer cells for 24 h cisplatin plus echistatin severely inhibits cell growth and activates apoptosis by upregulation of caspase-3 and -9 expressions. The effect was stronger than treatment cisplatin and echistatin alone. In this study, we have found that cisplatin plus echistatin treatment decreases collagen biosynthesis in MDA-MB-231 breast cancer cells stronger than the individual compounds. The inhibition was found to be dependent on the β 1 -integrin and IGF receptor activation. A significant reduction of ERK1/ERK2, AKT expression in cancer cells after cisplatin plus echistatin treatment was also found. The cancer cells treated by echistatin, cisplatin, and in particular the combination of both compounds drastically increased expression of NFκB transcription factor. Our results suggest that combined therapy cisplatin plus echistatin is a possible way to improve selectiveness of cisplatin. This

  5. Biphasic modulation of insulin receptor substrate-1 during goitrogenesis

    Directory of Open Access Journals (Sweden)

    R. Grozovsky

    2007-05-01

    Full Text Available Insulin receptor substrate-1 (IRS-1 is the main intracellular substrate for both insulin and insulin-like growth factor I (IGF-I receptors and is critical for cell mitogenesis. Thyrotropin is able to induce thyroid cell proliferation through the cyclic AMP intracellular cascade; however, the presence of either insulin or IGF-I is required for the mitogenic effect of thyroid-stimulating hormone (TSH to occur. The aim of the present study was to determine whether thyroid IRS-1 content is modulated by TSH in vivo. Strikingly, hypothyroid goitrous rats, which have chronically high serum TSH levels (control, C = 2.31 ± 0.28; methimazole (MMI 21d = 51.02 ± 6.02 ng/mL, N = 12 rats, when treated with 0.03% MMI in drinking water for 21 days, showed significantly reduced thyroid IRS-1 mRNA content. Since goiter was already established in these animals by MMI for 21 days, we also evaluated IRS-1 expression during goitrogenesis. Animals treated with MMI for different periods of time showed a progressive increase in thyroid weight (C = 22.18 ± 1.21; MMI 5d = 32.83 ± 1.48; MMI 7d = 31.1 ± 3.25; MMI 10d = 33.8 ± 1.25; MMI 14d = 45.5 ± 2.56; MMI 18d = 53.0 ± 3.01; MMI 21d = 61.9 ± 3.92 mg, N = 9-15 animals per group and serum TSH levels (C = 1.57 ± 0.2; MMI 5d = 9.95 ± 0.74; MMI 7d = 10.38 ± 0.84; MMI 10d = 17.72 ± 1.47; MMI 14d = 25.65 ± 1.23; MMI 18d = 35.38 ± 3.69; MMI 21d = 31.3 ± 2.7 ng/mL, N = 9-15 animals per group. Thyroid IRS-1 mRNA expression increased progressively during goitrogenesis, being significantly higher by the 14th day of MMI treatment, and then started to decline, reaching the lowest values by the 21st day, when a significant reduction was detected. In the liver of these animals, however, a significant decrease of IRS-1 mRNA was detected after 14 days of MMI treatment, a mechanism probably involved in the insulin resistance that occurs in hypothyroidism. The increase in IRS-1 expression during goitrogenesis may represent an

  6. Regulation of endocrine and paracrine sources of insulin-like growth factors and growth hormone receptor during compensatory growth in hybrid striped bass (Morone chrysops x Morone saxatilis)

    DEFF Research Database (Denmark)

    Picha, Matthew E; Turano, Marc J; Tipsmark, Christian K

    2008-01-01

    Compensatory growth (CG) is a period of growth acceleration that exceeds normal rates after animals are alleviated of certain growth-stunting conditions. In hybrid striped bass (HSB, Morone chrysops x M. saxatilis), 3 weeks of complete feed restriction results in a catabolic state that, when...... relieved, renders a subsequent phase of CG. The catabolic state was characterized by depressed levels of hepatic Type I and II GH receptor (Ghr1, Ghr2) and insulin-like growth factor-I (Igf-I) mRNA, along with considerable decreases in plasma IGF-I. The state of catabolism also resulted in significant...... declines in hepatic Igf-II mRNA and in circulating 40kDa IGF binding protein (IGFBP). Skeletal muscle expression of Ghr2 mRNA was significantly increased. Upon realimentation, specific growth rates (SGR) were significantly higher than sized-matched controls, indicating a period of CG. Hepatic Ghr1, Ghr2...

  7. Dynamics of the actin cytoskeleton mediates receptor cross talk: An emerging concept in tuning receptor signaling

    Science.gov (United States)

    Mattila, Pieta K.; Batista, Facundo D.

    2016-01-01

    Recent evidence implicates the actin cytoskeleton in the control of receptor signaling. This may be of particular importance in the context of immune receptors, such as the B cell receptor, where dysregulated signaling can result in autoimmunity and malignancy. Here, we discuss the role of the actin cytoskeleton in controlling receptor compartmentalization, dynamics, and clustering as a means to regulate receptor signaling through controlling the interactions with protein partners. We propose that the actin cytoskeleton is a point of integration for receptor cross talk through modulation of protein dynamics and clustering. We discuss the implication of this cross talk via the cytoskeleton for both ligand-induced and low-level constitutive (tonic) signaling necessary for immune cell survival. PMID:26833785

  8. Group I Metabotropic Glutamate Receptors

    DEFF Research Database (Denmark)

    Erichsen, Julie Ladeby; Blaabjerg, Morten; Bogetofte Thomasen, Helle

    2015-01-01

    is, however, needed to realise their therapeutic potential. Glutamate and group I metabotropic glutamate receptors (mGluRs) affect proliferation and survival of rodent NSCs both during embryonic and postnatal development. To investigate the role of group I mGluRs (mGluR1 and mGluR5) on human NSCs, we...... differentiated an immortalized, forebrain-derived stem cell line in the presence or absence of glutamate and with addition of either the group I mGluR agonist DHPG or the selective antagonists; MPEP (mGluR5) and LY367385 (mGluR1). Characterization of differentiated cells revealed that both mGluR1 and mGluR5 were...... present on the cells. Addition of glutamate to the growth medium significantly increased cell proliferation and reduced cell death, resulting in increased cell numbers. In the presence of glutamate, selective activation of group I mGluRs reduced gliogenesis, whereas selective inhibition of group I m...

  9. Endogenous Receptor Agonists: Resolving Inflammation

    Directory of Open Access Journals (Sweden)

    Gerhard Bannenberg

    2007-01-01

    Full Text Available Controlled resolution or the physiologic resolution of a well-orchestrated inflammatory response at the tissue level is essential to return to homeostasis. A comprehensive understanding of the cellular and molecular events that control the termination of acute inflammation is needed in molecular terms given the widely held view that aberrant inflammation underlies many common diseases. This review focuses on recent advances in the understanding of the role of arachidonic acid and ω-3 polyunsaturated fatty acids (PUFA–derived lipid mediators in regulating the resolution of inflammation. Using a functional lipidomic approach employing LC-MS-MS–based informatics, recent studies, reviewed herein, uncovered new families of local-acting chemical mediators actively biosynthesized during the resolution phase from the essential fatty acids eicosapentaenoic acid (EPA and docosahexaenoic acid (DHA. These new families of local chemical mediators are generated endogenously in exudates collected during the resolution phase, and were coined resolvins and protectins because specific members of these novel chemical families control both the duration and magnitude of inflammation in animal models of complex diseases. Recent advances on the biosynthesis, receptors, and actions of these novel anti-inflammatory and proresolving lipid mediators are reviewed with the aim to bring to attention the important role of specific lipid mediators as endogenous agonists in inflammation resolution.

  10. Teleost Chemokines and Their Receptors

    Directory of Open Access Journals (Sweden)

    Steve Bird

    2015-11-01

    Full Text Available Chemokines are a superfamily of cytokines that appeared about 650 million years ago, at the emergence of vertebrates, and are responsible for regulating cell migration under both inflammatory and physiological conditions. The first teleost chemokine gene was reported in rainbow trout in 1998. Since then, numerous chemokine genes have been identified in diverse fish species evidencing the great differences that exist among fish and mammalian chemokines, and within the different fish species, as a consequence of extensive intrachromosomal gene duplications and different infectious experiences. Subsequently, it has only been possible to establish clear homologies with mammalian chemokines in the case of some chemokines with well-conserved homeostatic roles, whereas the functionality of other chemokine genes will have to be independently addressed in each species. Despite this, functional studies have only been undertaken for a few of these chemokine genes. In this review, we describe the current state of knowledge of chemokine biology in teleost fish. We have mainly focused on those species for which more research efforts have been made in this subject, specially zebrafish (Danio rerio, rainbow trout (Oncorhynchus mykiss and catfish (Ictalurus punctatus, outlining which genes have been identified thus far, highlighting the most important aspects of their expression regulation and addressing any known aspects of their biological role in immunity. Finally, we summarise what is known about the chemokine receptors in teleosts and provide some analysis using recently available data to help characterise them more clearly.

  11. 5-HT7 receptor activation promotes an increase in TrkB receptor expression and phosphorylation

    Directory of Open Access Journals (Sweden)

    Anshula eSamarajeewa

    2014-11-01

    Full Text Available The serotonin (5-HT type 7 receptor is expressed throughout the CNS including cortical neurons. We have previously demonstrated that the application of 5-HT7 receptor agonists to primary hippocampal neurons and SH-SY5Y cells increases platelet-derived growth factor (PDGF receptor expression and promotes neuroprotection against N-methyl-D-aspartate-(NMDA-induced toxicity. The tropomyosin-related kinase B (TrkB receptor is one of the receptors for brain-derived neurotrophic factor (BDNF and is associated with neurodevelopmental and neuroprotective effects. Application of LP 12 to primary cerebral cortical cultures, SH-SY5Y cells, as well as the retinal ganglion cell line, RGC-5, increased both the expression of full length TrkB as well as its basal phosphorylation state at tyrosine 816. The increase in TrkB expression and phosphorylation was observed as early as 30 min after 5-HT7 receptor activation. In addition to full-length TrkB, kinase domain-deficient forms may be expressed and act as dominant-negative proteins towards the full length receptor. We have identified distinct patterns of TrkB isoform expression across our cell lines and cortical cultures. Although TrkB receptor expression is regulated by cyclic AMP and Gαs-coupled GPCRs in several systems, we demonstrate that, depending on the model system, pathways downstream of both Gαs and Gα12 are involved in the regulation of TrkB expression by 5-HT7 receptors. Given the number of psychiatric and degenerative diseases associated with TrkB/BDNF deficiency and the current interest in developing 5-HT7 receptor ligands as pharmaceuticals, identifying signaling relationships between these two receptors will aid in our understanding of the potential therapeutic effects of 5-HT7 receptor ligands.

  12. Acetylcholine Receptor: Complex of Homologous Subunits

    Science.gov (United States)

    Raftery, Michael A.; Hunkapiller, Michael W.; Strader, Catherine D.; Hood, Leroy E.

    1980-06-01

    The acetylcholine receptor from the electric ray Torpedo californica is composed of five subunits; two are identical and the other three are structurally related to them. Microsequence analysis of the four polypeptides demonstrates amino acid homology among the subunits. Further sequence analysis of both membrane-bound and Triton-solubilized, chromatographically purified receptor gave the stoichiometry of the four subunits (40,000:50,000:60,000:65,000 daltons) as 2:1:1:1, indicating that this protein is a pentameric complex with a molecular weight of 255,000 daltons. Genealogical analysis suggests that divergence from a common ancestral gene occurred early in the evolution of the receptor. This shared ancestry argues that each of the four subunits plays a functional role in the receptor's physiological action.

  13. Tachykinins and tachykinin receptors: a growing family.

    Science.gov (United States)

    Pennefather, Jocelyn N; Lecci, Alessandro; Candenas, M Luz; Patak, Eva; Pinto, Francisco M; Maggi, Carlo Alberto

    2004-02-06

    The peptides of the tachykinin family are widely distributed within the mammalian peripheral and central nervous systems and play a well-recognized role as excitatory neurotransmitters. Currently, the concept that tachykinins act exclusively as neuropeptides is being challenged, since the best known members of the family, substance P, neurokinin A and neurokinin B, are also present in non-neuronal cells and in non-innervated tissues. Moreover, the recently cloned mammalian tachykinins hemokinin-1 and endokinins are primarily expressed in non-neuronal cells, suggesting a widespread distribution and important role for these peptides as intercellular signaling molecules. The biological actions of tachykinins are mediated through three types of receptors denoted NK(1), NK(2) and NK(3) that belong to the family of G protein-coupled receptors. The identification of additional tachykinins has reopened the debate of whether more tachykinin receptors exist. In this review, we summarize the current knowledge of tachykinins and their receptors.

  14. Lactate Transport and Receptor Actions in Retina

    DEFF Research Database (Denmark)

    Kolko, Miriam; Vosborg, Fia; Henriksen, Jens Ulrik Lütken

    2016-01-01

    In retina, like in brain, lactate equilibrates across cell membranes via monocarboxylate transporters and in the extracellular space by diffusion, forming a basis for the action of lactate as a transmitter of metabolic signals. In the present paper, we argue that the lactate receptor GPR81, also...... known as HCAR1, may contribute importantly to the control of retinal cell functions in health and disease. GPR81, a G-protein coupled receptor, is known to downregulate cAMP both in adipose and nervous tissue. The receptor also acts through other down-stream mechanisms to control functions...... reveal high GPR81 mRNA in retina and indicate GPR81 localization in Müller cells and retinal ganglion cells. Moreover, monocarboxylate transporters are expressed in retinal cells. We envision that lactate receptors and transporters could be useful future targets of novel therapeutic strategies to protect...

  15. Molecular Mechanisms of Dopamine Receptor Mediated Neuroprotection

    National Research Council Canada - National Science Library

    Sealfon, Stuart

    2000-01-01

    ... of the cellular changes characteristic of this process. Evidence from our laboratory and others suggest that activation of dopamine receptors can oppose the induction of apoptosis in dopamine neurons...

  16. Agonism and antagonism at the insulin receptor

    DEFF Research Database (Denmark)

    Knudsen, Louise; Hansen, Bo Falck; Jensen, Pia

    2012-01-01

    Insulin can trigger metabolic as well as mitogenic effects, the latter being pharmaceutically undesirable. An understanding of the structure/function relationships between insulin receptor (IR) binding and mitogenic/metabolic signalling would greatly facilitate the preclinical development of new...... insulin analogues. The occurrence of ligand agonism and antagonism is well described for G protein-coupled receptors (GPCRs) and other receptors but in general, with the exception of antibodies, not for receptor tyrosine kinases (RTKs). In the case of the IR, no natural ligand or insulin analogue has been...... shown to exhibit antagonistic properties, with the exception of a crosslinked insulin dimer (B29-B'29). However, synthetic monomeric or dimeric peptides targeting sites 1 or 2 of the IR were shown to be either agonists or antagonists. We found here that the S961 peptide, previously described to be an IR...

  17. Agonist induction, conformational selection, and mutant receptors.

    Science.gov (United States)

    Giraldo, Jesús

    2004-01-02

    Current models of receptor activation are based on either of two basic mechanisms: agonist induction or conformational selection. The importance of one pathway relative to the other is controversial. In this article, the impossibility of distinguishing between the two mechanisms under a thermodynamic approach is shown. The effect of receptor mutation on the constants governing ligand-receptor equilibria is discussed. The two-state model of agonism both in its original formulation (one cycle) and including multiple active states (multiple cycles) is used. Pharmacological equations for the double (two cycles) two-state model are derived. The simulations performed suggest that the double two-state model of agonism can be a useful model for assessing quantitatively the changes in pharmacological activity following receptor mutation.

  18. Brain nuclear receptors and body weight regulation

    Science.gov (United States)

    Neural pathways, especially those in the hypothalamus, integrate multiple nutritional, hormonal, and neural signals, resulting in the coordinated control of body weight balance and glucose homeostasis. Nuclear receptors (NRs) sense changing levels of nutrients and hormones, and therefore play essent...

  19. Ecdysteroid receptors in Drosophila melanogaster adult females

    Science.gov (United States)

    Ecdysteroid receptors were identified and partially characterized from total cell extracts of whole animals and dissected tissues from Drosophila melanogaster adult females. Binding studies indicated the presence of two ecdysteroid binding components having high affinity and specificity consistent w...

  20. Familial hypocalciuric hypercalcemia and calcium sensing receptor

    DEFF Research Database (Denmark)

    Mrgan, Monija; Nielsen, Sanne; Brixen, Kim

    2014-01-01

    Familial hypocalciuric hypercalcemia (FHH) is a lifelong, benign autosomal dominant disease characterized by hypercalcemia, normal to increased parathyroid hormone level, and a relatively low renal calcium excretion. Inactivation of the calcium-sensing receptor in heterozygous patients results in...

  1. Clinical and Genomic Crosstalk between Glucocorticoid Receptor and Estrogen Receptor α In Endometrial Cancer

    Directory of Open Access Journals (Sweden)

    Jeffery M. Vahrenkamp

    2018-03-01

    Full Text Available Summary: Steroid hormone receptors are simultaneously active in many tissues and are capable of altering each other’s function. Estrogen receptor α (ER and glucocorticoid receptor (GR are expressed in the uterus, and their ligands have opposing effects on uterine growth. In endometrial tumors with high ER expression, we surprisingly found that expression of GR is associated with poor prognosis. Dexamethasone reduced normal uterine growth in vivo; however, this growth inhibition was abolished in estrogen-induced endometrial hyperplasia. We observed low genomic-binding site overlap when ER and GR are induced with their respective ligands; however, upon simultaneous induction they co-occupy more sites. GR binding is altered significantly by estradiol with GR recruited to ER-bound loci that become more accessible upon estradiol induction. Gene expression responses to co-treatment were more similar to estradiol but with additional regulated genes. Our results suggest phenotypic and molecular interplay between ER and GR in endometrial cancer. : Estrogen receptor α (ER and glucocorticoid receptor (GR are expressed in the uterus and have differential effects on growth. Vahrenkamp et al. find that expression of both receptors is associated with poor outcome in endometrial cancer and that simultaneous induction of ER and GR leads to molecular interplay between the receptors. Keywords: estrogen receptor, glucocorticoid receptor, endometrial cancer

  2. Evidence for Heterodimerization and Functional Interaction of the Angiotensin Type 2 Receptor and the Receptor MAS

    DEFF Research Database (Denmark)

    Leonhardt, Julia; Villela, Daniel C.; Teichmann, Anke

    2017-01-01

    The angiotensin type 2 receptor (AT2R) and the receptor MAS are receptors of the protective arm of the renin-angiotensin system. They mediate strikingly similar actions. Moreover, in various studies, AT2R antagonists blocked the effects of MAS agonists and vice versa. Such cross-inhibition may......, subfamily C-member 6. Dimerization of the AT2R was abolished when it was mutated at cysteine residue 35. AT2R and MAS stimulation with the respective agonists, Compound 21 or angiotensin-(1-7), significantly induced CX3C chemokine receptor-1 messenger RNA expression. Effects of each agonist were blocked...

  3. Determination of co-receptor usage of HIV-1

    NARCIS (Netherlands)

    Schuitemaker, Hanneke; Kootstra, Neeltje A.

    2005-01-01

    In addition to CD4, HIV-1 uses chemokine receptors for entry in their target cells. The most important chemokine receptors in this respect are beta-chemokine receptor 5 (CCR5) and alpha-chemokine receptor 4 (CXCR4). Coreceptor usage is an important feature of the biological phenotype of HIV-1

  4. Dopamine receptors - physiological understanding to therapeutic intervention potential

    NARCIS (Netherlands)

    Emilien, G; Maloteaux, JM; Hoogenberg, K; Cragg, S

    1999-01-01

    There are two families of dopamine (DA) receptors, called D(1) and D(2), respectively. The D(1) family consists of D(1)- and D(5)-receptor subtypes and the D(2) family consists of D(2)-, D(3)-, and D(4)-receptor subtypes. The amino acid sequences of these receptors show that they all belong to a

  5. A recipe for ridding synapses of the ubiquitous AMPA receptor.

    Science.gov (United States)

    Turrigiano, Gina G

    2002-12-01

    Getting AMPA receptors into and out of synapses represents an important mechanism for changing synaptic strength, but the signals that target AMPA receptors for removal from the synaptic membrane are incompletely understood. A recent study in Ceanorhabditis elegans suggests that ubiquitination of AMPA receptors is one important signal that targets these receptors for endocytosis.

  6. NK-1 receptor antagonists as anti-cancer drugs

    Indian Academy of Sciences (India)

    The substance P (SP)/neurokinin (NK)-1 receptor system plays an important role in cancer. SP promotes the proliferation of tumour cells, angiogenesis and the migration of tumour cells. We review the involvement of SP, the NK-1 receptor and NK-1 receptor antagonists in cancer. Tumour cells overexpress NK-1 receptors, ...

  7. The MC4 receptor and control of appetite

    NARCIS (Netherlands)

    Adan, R. A. H.; Tiesjema, B.; Hillebrand, J. J. G.; La Fleur, S. E.; Kas, M. J. H.; de Krom, M.

    2006-01-01

    Mutations in the human melanocortin (MC)4 receptor have been associated with obesity, which underscores the relevance of this receptor as a drug target to treat obesity. Infusion of MC4R agonists decreases food intake, whereas inhibition of MC receptor activity by infusion of an MC receptor

  8. Agonist discrimination between AMPA receptor subtypes

    DEFF Research Database (Denmark)

    Coquelle, T; Christensen, J K; Banke, T G

    2000-01-01

    The lack of subtype-selective compounds for AMPA receptors (AMPA-R) led us to search for compounds with such selectivity. Homoibotenic acid analogues were investigated at recombinant GluR1o, GluR2o(R), GluR3o and GluR1o + 3o receptors expressed in Sf9 insect cells and affinities determined in [3H...

  9. Methodological aspects on drug receptor binding analysis

    International Nuclear Information System (INIS)

    Wahlstroem, A.

    1978-01-01

    Although drug receptors occur in relatively low concentrations, they can be visualized by the use of appropriate radioindicators. In most cases the procedure is rapid and can reach a high degree of accuracy. Specificity of the interaction is studied by competition analysis. The necessity of using several radioindicators to define a receptor population is emphasized. It may be possible to define isoreceptors and drugs with selectivity for one isoreceptor. (Author)

  10. The Angiotensin AT2 Receptor

    DEFF Research Database (Denmark)

    Unger, Thomas; Steckelings, Ulrike M.; Dzau, Victor J.

    2015-01-01

    Since its discovery, 25 years ago, the angiotensin AT2 receptor (AT2R) has puzzled the scientific community because of its distinct -localization, regulation, signaling pathways, and biological effects separating it clearly from the classical features of the renin-angiotensin...... system (RAS) mediated by the angiotensin AT1 receptor. Intensive research over the years has revealed major characteristics of the AT2R as a modulatory player involved in antiproliferation, anti-inflammation, natriuresis, neuroregeneration, and apoptosis, that is, -biological...

  11. Moth sex pheromone receptors and deceitful parapheromones.

    Directory of Open Access Journals (Sweden)

    Pingxi Xu

    Full Text Available The insect's olfactory system is so selective that male moths, for example, can discriminate female-produced sex pheromones from compounds with minimal structural modifications. Yet, there is an exception for this "lock-and-key" tight selectivity. Formate analogs can be used as replacement for less chemically stable, long-chain aldehyde pheromones, because male moths respond physiologically and behaviorally to these parapheromones. However, it remained hitherto unknown how formate analogs interact with aldehyde-sensitive odorant receptors (ORs. Neuronal responses to semiochemicals were investigated with single sensillum recordings. Odorant receptors (ORs were cloned using degenerate primers, and tested with the Xenopus oocyte expression system. Quality, relative quantity, and purity of samples were evaluated by gas chromatography and gas chromatography-mass spectrometry. We identified olfactory receptor neurons (ORNs housed in trichoid sensilla on the antennae of male navel orangeworm that responded equally to the main constituent of the sex pheromone, (11Z,13Z-hexadecadienal (Z11Z13-16Ald, and its formate analog, (9Z,11Z-tetradecen-1-yl formate (Z9Z11-14OFor. We cloned an odorant receptor co-receptor (Orco and aldehyde-sensitive ORs from the navel orangeworm, one of which (AtraOR1 was expressed specifically in male antennae. AtraOR1•AtraOrco-expressing oocytes responded mainly to Z11Z13-16Ald, with moderate sensitivity to another component of the sex pheromone, (11Z,13Z-hexadecadien-1-ol. Surprisingly, this receptor was more sensitive to the related formate than to the natural sex pheromone. A pheromone receptor from Heliothis virescens, HR13 ( = HvirOR13 showed a similar profile, with stronger responses elicited by a formate analog than to the natural sex pheromone, (11Z-hexadecenal thus suggesting this might be a common feature of moth pheromone receptors.

  12. External Imaging of Cerebral Muscarinic Acetylcholine Receptors

    Science.gov (United States)

    Eckelman, William C.; Reba, Richard C.; Rzeszotarski, Waclaw J.; Gibson, Raymond E.; Hill, Thomas; Holman, B. Leonard; Budinger, Thomas; Conklin, James J.; Eng, Robert; Grissom, Michael P.

    1984-01-01

    A radioiodinated ligand that binds to muscarinic acetylcholine receptors was shown to distribute in the brain by a receptor-mediated process. With single-photon-emission imaging techniques, radioactivity was detected in the cerebrum but not in the cerebellum, whereas with a flow-limited radiotracer, radioactivity was detected in cerebrum and cerebellum. Single-photon-emission computed tomography showed good definition of the caudate putamen and cortex in man.

  13. Angiotensin Receptors, Autoimmunity, and Preeclampsia1

    OpenAIRE

    Xia, Yang; Zhou, Cissy Chenyi; Ramin, Susan M.; Kellems, Rodney E.

    2007-01-01

    Preeclampsia is a pregnancy-induced hypertensive disorder that causes substantial maternal and fetal morbidity and mortality. Despite being a leading cause of maternal death and a major contributor to maternal and perinatal morbidity, the mechanisms responsible for the pathogenesis of preeclampsia are poorly understood. Recent studies indicate that women with preeclampsia have autoantibodies that activate the angiotensin receptor, AT1, and that autoantibody-mediated receptor activation contri...

  14. Neurokinin-1 receptor activation in globus pallidus

    Directory of Open Access Journals (Sweden)

    Lei Chen

    2009-10-01

    Full Text Available The undecapeptide substance P has been demonstrated to modulate neuronal activity in a number of brain regions by acting on neurokinin-1 receptors. Anatomical studies revealed a moderate level of neurokinin-1 receptor in rat globus pallidus. To determine the electrophysiological effects of neurokinin-1 receptor activation in globus pallidus, whole-cell patch-clamp recordings were performed in the present study. Under current-clamp recordings, neurokinin-1 receptor agonist, [Sar9, Met(O211] substance P (SM-SP at 1 μM, depolarized globus pallidus neurons and increased their firing rate. Consistently, SM-SP induced an inward current under voltage-clamp recording. The depolarization evoked by SM-SP persisted in the presence of tetrodotoxin, glutamate and GABA receptor antagonists, indicating its direct postsynaptic effects. The neurokinin-1 receptor antagonist, SR140333B, could block SM-SP-induced depolarization. Further experiments showed that suppression of potassium conductance was the predominant ionic mechanism of SM-SP-induced depolarization. To determine if neurokinin-1 receptor activation exerts any effects on GABAergic and glutamatergic neurotransmission, the action of SM-SP on synaptic currents was studied. SM-SP significantly increased the frequency of spontaneous inhibitory postsynaptic currents, but only induced a transient increase in the frequency of miniature inhibitory postsynaptic currents. No change was observed in both spontaneous and miniature excitatory postsynaptic currents. Based on the direct excitatory effects of SM-SP on pallidal neurons, we hypothesize that neurokinin-1 receptor activation in globus pallidus may be involved in the beneficial effect of substance P in Parkinson’s disease.

  15. Toll-like receptors in skin

    OpenAIRE

    Miller, Lloyd S.

    2008-01-01

    The skin not only plays an important role as a physical barrier between the host and the environment, but also plays a key immunologic role in sensing and responding to invading pathogens from the environment. Toll-like receptors (TLRs), which are expressed by many different types of cells in human skin, have been found to be important pattern recognition receptors that are involved in recognizing components of microbial pathogens and initiating and instructing cutaneous immune responses. Thi...

  16. Cricket body size is altered by systemic RNAi against insulin signaling components and epidermal growth factor receptor.

    Science.gov (United States)

    Dabour, Noha; Bando, Tetsuya; Nakamura, Taro; Miyawaki, Katsuyuki; Mito, Taro; Ohuchi, Hideyo; Noji, Sumihare

    2011-09-01

    A long-standing problem of developmental biology is how body size is determined. In Drosophila melanogaster, the insulin/insulin-like growth factor (I/IGF) and target of rapamycin (TOR) signaling pathways play important roles in this process. However, the detailed mechanisms by which insect body growth is regulated are not known. Therefore, we have attempted to utilize systemic nymphal RNA interference (nyRNAi) to knockdown expression of insulin signaling components including Insulin receptor (InR), Insulin receptor substrate (chico), Phosphatase and tensin homologue (Pten), Target of rapamycin (Tor), RPS6-p70-protein kinase (S6k), Forkhead box O (FoxO) and Epidermal growth factor receptor (Egfr) and observed the effects on body size in the Gryllus bimaculatus cricket. We found that crickets treated with double-stranded RNA (dsRNA) against Gryllus InR, chico, Tor, S6k and Egfr displayed smaller body sizes, while Gryllus FoxO nyRNAi-ed crickets exhibited larger than normal body sizes. Furthermore, RNAi against Gryllus chico and Tor displayed slow growth and RNAi against Gryllus chico displayed longer lifespan than control crickets. Since no significant difference in ability of food uptake was observed between the Gryllus chico(nyRNAi) nymphs and controls, we conclude that the adult cricket body size can be altered by knockdown of expressions of Gryllus InR, chico, Tor, S6k, FoxO and Egfr by systemic RNAi. Our results suggest that the cricket is a promising model to study mechanisms underlying controls of body size and life span with RNAi methods. © 2011 The Authors. Development, Growth & Differentiation © 2011 Japanese Society of Developmental Biologists.

  17. Beta adrenergic receptors in human cavernous tissue

    Energy Technology Data Exchange (ETDEWEB)

    Dhabuwala, C.B.; Ramakrishna, C.V.; Anderson, G.F.

    1985-04-01

    Beta adrenergic receptor binding was performed with /sup 125/I iodocyanopindolol on human cavernous tissue membrane fractions from normal tissue and transsexual procedures obtained postoperatively, as well as from postmortem sources. Isotherm binding studies on normal fresh tissues indicated that the receptor density was 9.1 fmoles/mg. with a KD of 23 pM. Tissue stored at room temperature for 4 to 6 hours, then at 4C in saline solution for 19 to 20 hours before freezing showed no significant changes in receptor density or affinity, and provided evidence for the stability of postmortem tissue obtained within the same time period. Beta receptor density of 2 cavernous preparations from transsexual procedures was not significantly different from normal control tissues, and showed that high concentrations of estrogen received by these patients had no effect on beta adrenergic receptor density. Displacement of /sup 125/iodocyanopindolol by 5 beta adrenergic agents demonstrated that 1-propranolol had the greatest affinity followed by ICI 118,551, zinterol, metoprolol and practolol. When the results of these displacement studies were subjected to Scatfit, non- linear regression line analysis, a single binding site was described. Based on the relative potency of the selective beta adrenergic agents it appears that these receptors were of the beta 2 subtype.

  18. ROR-Family Receptor Tyrosine Kinases.

    Science.gov (United States)

    Stricker, Sigmar; Rauschenberger, Verena; Schambony, Alexandra

    2017-01-01

    ROR-family receptor tyrosine kinases form a small subfamily of receptor tyrosine kinases (RTKs), characterized by a conserved, unique domain architecture. ROR RTKs are evolutionary conserved throughout the animal kingdom and act as alternative receptors and coreceptors of WNT ligands. The intracellular signaling cascades activated downstream of ROR receptors are diverse, including but not limited to ROR-Frizzled-mediated activation of planar cell polarity signaling, RTK-like signaling, and antagonistic regulation of WNT/β-Catenin signaling. In line with their diverse repertoire of signaling functions, ROR receptors are involved in the regulation of multiple processes in embryonic development such as development of the axial and paraxial mesoderm, the nervous system and the neural crest, the axial and appendicular skeleton, and the kidney. In humans, mutations in the ROR2 gene cause two distinct developmental syndromes, recessive Robinow syndrome (RRS; MIM 268310) and dominant brachydactyly type B1 (BDB1; MIM 113000). In Robinow syndrome patients and animal models, the development of multiple organs is affected, whereas BDB1 results only in shortening of the distal phalanges of fingers and toes, reflecting the diversity of functions and signaling activities of ROR-family RTKs. In this chapter, we give an overview on ROR receptor structure and function. We discuss their signaling functions and role in vertebrate embryonic development with a focus on those developmental processes that are affected by mutations in the ROR2 gene in human patients. © 2017 Elsevier Inc. All rights reserved.

  19. Functional reconstitution of the glycine receptor

    International Nuclear Information System (INIS)

    Garcia-Calvo, M.; Ruiz-Gomez, A.; Vazquez, J.; Morato, E.; Valdivieso, F.; Mayor, F. Jr.

    1989-01-01

    The functional reconstitution of the chloride channel coupled glycine receptor is described. Glycine receptors were purified from the cholate extract of rat spinal cord membranes by affinity chromatography and incorporated into phospholipid vesicles by the addition of phosphatidylcholine and removal of detergent by gel filtration. The reconstituted vesicles showed the same polypeptide composition as the purified receptor. The pharmacological characteristics of the glycine receptor were also preserved in the proteoliposomes, as demonstrated by the displacement of [ 3 H]strychnine binding by several glycinergic ligands and by photoaffinity labeling experiments. In order to observe functional responses (i.e., specific agonist-induced anion translocation), the authors have developed an assay based on the fluorescence quenching of an anion-sensitive entrapped probe, SPQ [6-methoxy-N-(3-sulfopropyl)quinolinium]. Reconstituted vesicles were loaded with the fluorescent probe during a freeze-thaw-sonication cycle in the presence of added liposomes containing cholesterol. In such a reconstituted system, glycine receptor agonists are able to increase the rate of anion influx into the vesicles. The action of agonists is blocked by the simultaneous presence of strychnine or other glycine antagonists. The results show that the purified 48,000- and 58,000-dalton polypeptides reconstituted into phospholipid vesicles can bind ligands and promote specific ion translocation in a way similar to the glycine receptor in its native environment

  20. Vitamin D receptors and parathyroid glands.

    Science.gov (United States)

    Landry, Christine S; Ruppe, Mary D; Grubbs, Elizabeth G

    2011-01-01

    To describe the function and metabolism of the vitamin D hormone and the role of the vitamin D receptor and the calcium-sensing receptor in the secretion of parathyroid hormone. A review of the literature was undertaken regarding the function and metabolism of vitamin D; the role of the vitamin D receptor and calcium-sensing receptor in the secretion of parathyroid hormone; and the contemporary research regarding the interaction of vitamin D and parathyroid hormone in patients with vitamin D deficiency, primary hyperparathyroidism, and secondary hyperparathyroidism. Over the last several years, great interest has been generated about the interaction of vitamin D and the parathyroid glands, gastrointestinal tract, kidney, and bone in relation to calcium and parathyroid hormone levels. Vitamin D has an important role in calcium and parathyroid hormone metabolism. Likewise, the vitamin D axis appears to be involved with the development of both primary and secondary hyperparathyroidism. The specific mechanism by which vitamin D interacts with the parathyroid gland to bring about observed effects is not yet fully understood. Future studies investigating the relationship of the vitamin D receptor, calcium-sensing receptor, and parathyroid glands are needed to enhance our knowledge of vitamin D deficiency and primary and secondary vitamin D deficiency.