Abnormalities of IGF-I signaling in the pathogenesis of diseases of the bone, brain, and fetoplacental unit in humans

2008 ◽  
Vol 295 (5) ◽  
pp. E991-E999 ◽  
Author(s):  
Luigi Laviola ◽  
Annalisa Natalicchio ◽  
Sebastio Perrini ◽  
Francesco Giorgino
Keyword(s):  
Neurodegenerative Disorders ◽  
Intracellular Signaling ◽  
Bone Growth ◽  
Muscle Metabolism ◽  
Signaling Cascades ◽  
Tissue Formation ◽  
Cellular Effects ◽  
Prenatal Growth ◽  
Igf I ◽  
Review Current

IGF-I action is essential for the regulation of tissue formation and remodeling, bone growth, prenatal growth, brain development, and muscle metabolism. Cellular effects of IGF-I are mediated through the IGF-I receptor, a transmembrane tyrosine kinase that phosphorylates intracellular substrates, resulting in the activation of multiple intracellular signaling cascades. Dysregulation of IGF-I actions due to impairment in the postreceptor signaling machinery may contribute to multiple diseases in humans. This article will review current information on IGF-I signaling and illustrate recent results demonstrating how impaired IGF-I signaling and action may contribute to the pathogenesis of human diseases, including osteoporosis, neurodegenerative disorders, and reduced fetal growth in utero.

Parathyroid Hormone in the Regulation of Bone Growth and Resorption in Health and Disease

2021 ◽  
Vol 76 (5) ◽  
pp. 506-517
Author(s):  
Maria V. Vorontsova ◽  
Konstantin Y. Kulebyakin ◽  
Nadezhda V. Makazan ◽  
Leila S. Sozaeva ◽  
Pyotr A. Tyurin-Kuzmin
Keyword(s):  
Parathyroid Hormone ◽  
Bone Tissue ◽  
Intracellular Signaling ◽  
Molecular Mechanisms ◽  
Bone Growth ◽  
The Body ◽  
Signaling Cascades ◽  
Main Body ◽  
Bone Homeostasis ◽  
Cellular Mechanisms

Parathyroid hormone (PTH) is a key hormone responsible for regulation of calcium homeostasis in the body. Since the main body calcium depot is bone tissue, PTH has a decisive effect on its homeostasis. In this case, the hormone can activate both bone formation and resorption. Thus, PTH can ensure the conjugation of anabolic and catabolic processes, which is necessary for the renewal of bone tissue, which is had to function under constant mechanical stress. At the same time, the use of PTH in medical practice is rather small, despite its high potential as a basis for the treatment of various pathologies associated with impaired bone homeostasis. Presented review, describes the intracellular signaling cascades and molecular mechanisms that underlie the action of PTH on bone tissue cells, and intracellular signaling cascades are described. A separate section examines the cellular mechanisms of the action of PTH on bone homeostasis, discusses how the effect of the hormone on different types of cells provides an interface between the processes of synthesis and resorption. In addition, the review examines diseases associated with impaired bone homeostasis, as well as the role of PTH and impaired signaling in their etiology.

Longitudinal bone growth in vitro: effects of insulin-like growth factor I and growth hormone

1991 ◽  
Vol 124 (5) ◽  
pp. 602-607 ◽  
Author(s):  
Ben A. A. Scheven ◽  
Nicola J. Hamilton
Keyword(s):  
Growth Hormone ◽  
Growth Factor ◽  
Bone Growth ◽  
Long Bone ◽  
Long Bones ◽  
Insulin Like Growth Factor ◽  
Serum Free ◽  
Factor I ◽  
Igf I

Abstract. Longitudinal growth was studied using an in vitro model system of intact rat long bones. Metatarsal bones from 18- and 19-day-old rat fetuses, entirely (18 days) or mainly (19 days) composed of chondrocytes, showed a steady rate of growth and radiolabelled thymidine incorporation for at least 7 days in serum-free media. Addition of recombinant human insulin-like growth factor-I to the culture media resulted in a direct stimulation of the longitudinal growth. Recombinant human growth hormone was also able to stimulate bone growth, although this was generally accomplished after a time lag of more than 2 days. A monoclonal antibody to IGF-I abolished both the IGF-I and GH-stimulated growth. However, the antibody had no effect on the growth of the bone explants in control, serum-free medium. Unlike the fetal long bones, bones from 2-day-old neonatal rats were arrested in their growth after 1-2 days in vitro. The neonatal bones responded to IGF-I and GH in a similar fashion as the fetal bones. Thus in this study in vitro evidence of a direct effect of GH on long bone growth via stimulating local production of IGF by the growth plate chondrocytes is presented. Furthermore, endogenous growth factors, others than IGFs, appear to play a crucial role in the regulation of fetal long bone growth.

scholarly journals Prospects for use of peptides and their derivatives, structurally corresponding to the G protein-coupled receptors, in medicine

2015 ◽  
Vol 61 (1) ◽  
pp. 19-29 ◽  
Author(s):  
A.O. Shpakov ◽  
E.A. Shpakova
Keyword(s):  
G Protein ◽  
Intracellular Signaling ◽  
High Efficiency ◽  
Clinical Medicine ◽  
Inflammatory Diseases ◽  
G Protein Coupled Receptors ◽  
Signaling Cascades ◽  
G Protein Coupled

The regulation of signaling pathways involved in the control of many physiological functions is carried out via the heterotrimeric G protein-coupled receptors (GPCR). The search of effective and selective regulators of GPCR and intracellular signaling cascades coupled with them is one of the important problems of modern fundamental and clinical medicine. Recently data suggest that synthetic peptides and their derivatives, structurally corresponding to the intracellular and transmembrane regions of GPCR, can interact with high efficiency and selectivity with homologous receptors and influence, thus, the functional activity of intracellular signaling cascades and fundamental cellular processes controlled by them. GPCR-peptides are active in both in vitro and in vivo. They regulate hematopoiesis, angiogenesis and cell proliferation, inhibit tumor growth and metastasis, and prevent the inflammatory diseases and septic shock. These data show greatest prospects in the development of the new generations of drugs based on GPCR-derived peptides, capable of regulating the important functions of the organism.

scholarly journals High resolution AKT signaling in individual cells

2018 ◽  
Author(s):  
Sean M. Gross ◽  
Mark A. Dane ◽  
Elmar Bucher ◽  
Laura M. Heiser
Keyword(s):  
Single Cell ◽  
Intracellular Signaling ◽  
Time Course ◽  
Dynamic Range ◽  
Individual Cell ◽  
Akt Signaling ◽  
Live Cells ◽  
Theoretic Approach ◽  
Wide Range ◽  
Igf I

AbstractCells sense and respond to their environment by activating distinct intracellular signaling pathways, however an individual cell’s ability to faithfully transmit and discriminate environmental signals is thought to be limited. To assess the fidelity of signal transmission in the PI3K-AKT signaling pathway, we first developed an optimized genetically encoded sensor that had an increased dynamic range and reduced variation under basal conditions. We then used this reporter to track responses to varying doses of IGF-I in live cells and found that signaling responses from individual cells overlapped across a wide range of IGF-I doses, suggesting limited transmission accuracy. However, further analysis of individual cell traces revealed that responses were constant over time without stochastic fluctuations. We devised a new information theoretic approach to calculate the channel capacity using variance of the single cell time course data‐‐rather than population-level variance as has been previously used—and predicted that cells were capable of discriminating multiple growth factor doses. We validated these predictions by tracking individual cell responses to multiple IGF-I doses and found that cells can accurately distinguish at least four different IGF-I concentrations, as demonstrated by their distinct responses. Furthermore, we found a similar discriminatory ability to pathway inhibition, as assessed by responses to the PI3K inhibitor alpelisib. Our studies indicate that cells can faithfully transmit an IGF-I input into a down-stream signaling response and that heterogeneous responses result from variation in the input-output relation across the population. These observations reveal the importance of viewing each cell as having its own communication channel and underscore the importance of understanding responses at the single cell level.

scholarly journals Visfatin: A Possible Role in Cardiovasculo-Metabolic Disorders

Cells ◽  
2020 ◽  
Vol 9 (11) ◽  
pp. 2444
Author(s):  
Ali Dakroub ◽  
Suzanne A. Nasser ◽  
Nour Younis ◽  
Humna Bhagani ◽  
Yusra Al-Dhaheri ◽  
...  
Keyword(s):  
Nicotinamide Adenine Dinucleotide ◽  
Intracellular Signaling ◽  
Skeletal Muscles ◽  
Metabolic Disorders ◽  
Metabolic Diseases ◽  
Signaling Cascades ◽  
Nicotinamide Phosphoribosyltransferase ◽  
Enhancing Factor ◽  
Cell Colony

Visfatin/NAMPT (nicotinamide phosphoribosyltransferase) is an adipocytokine with several intriguing properties. It was first identified as pre-B-cell colony-enhancing factor but turned out to possess enzymatic functions in nicotinamide adenine dinucleotide biosynthesis, with ubiquitous expression in skeletal muscles, liver, cardiomyocytes, and brain cells. Visfatin exists in an intracellular (iNAMPT) and extracellular (eNAMPT) form. Intracellularly, visfatin/iNAMPT plays a regulatory role in NAD+ biosynthesis and thereby affects many NAD-dependent proteins such as sirtuins, PARPs, MARTs and CD38/157. Extracellularly, visfatin is associated with many hormone-like signaling pathways and activates some intracellular signaling cascades. Importantly, eNAMPT has been associated with several metabolic disorders including obesity and type 1 and 2 diabetes. In this review, a brief overview about visfatin is presented with special emphasis on its relevance to metabolic diseases. Visfatin/NAMPT appears to be a unique molecule with clinical significance with a prospective promising diagnostic, prognostic, and therapeutic applications in many cardiovasculo-metabolic disorders.

Herbal Medicines with Antiviral Activity Against the Influenza Virus, a Systematic Review

2018 ◽  
Vol 46 (08) ◽  
pp. 1663-1700 ◽  
Author(s):  
Ju-Young Lee ◽  
Michael Edward C. Abundo ◽  
Chang-Won Lee
Keyword(s):  
Influenza Virus ◽  
Antiviral Activity ◽  
Nuclear Export ◽  
Intracellular Signaling ◽  
Mapk Pathway ◽  
Well Being ◽  
Signaling Cascades ◽  
Herbal Extracts ◽  
Replication Process ◽  
Antiviral Effects

The rapidly changing influenza virus has remained a consistent threat to the well-being of a variety of species on the planet. Influenza virus’ high mutation rate has allowed the virus to rapidly and continuously evolve, as well as generate new strains that are resistant to the current commercially available antivirals. Thus, the increased resistance has compelled the scientific community to explore alternative compounds that have antiviral effects against influenza virus. In this paper, the authors systematically review numerous herbal extracts that were shown to have antiviral effects against the virus. Specifically, the herbal antiviral targets mainly include hemagglutinin, neuraminidase and matrix 2 proteins. In some instances, herbal extracts inhibited the replication of oseltamivir-resistant strains and certain pentacyclic triterpenes exhibited higher antiviral activity than oseltamivir. This paper also explores the possibility of targeting various host-cell signaling pathways that are utilized by the virus during its replication process. Infected cell pathways are hijacked by intracellular signaling cascades such as NF-kB signaling, PI3K/Akt pathway, MAPK pathway and PKC/PKR signaling cascades. Herbal antivirals have been shown to target these pathways by suppressing nuclear export of influenza vRNP and thus inhibiting the phosphorylation signaling cascade. In conclusion, copious amounts of herbal antivirals have been shown to inhibit influenza virus, however further studies are needed for these new compounds to be up to modern pharmacological standards.

Modulation of growth factor incorporation into ECM of human osteoblast-like cells in vitro by 17 beta-estradiol

1994 ◽  
Vol 267 (6) ◽  
pp. E990-E1001 ◽  
Author(s):  
M. Slater ◽  
J. Patava ◽  
K. Kingham ◽  
R. S. Mason
Keyword(s):  
Growth Factors ◽  
Growth Factor ◽  
Transforming Growth Factor Beta ◽  
Bone Growth ◽  
Transforming Growth Factor ◽  
Bone Matrix ◽  
Tgf Beta ◽  
Subsequent Formation ◽  
Igf I

Human fetal osteoblast-like cells formed a regular multilayered structure in vitro with an extensive collagen-based extracellular matrix. With colloidal gold immunocytochemistry, labels for alkaline phosphatase and osteocalcin were distributed in a relatively diffuse pattern, in contrast to the bone growth factors, insulin-like growth factors I and II (IGF-I and IGF-II), transforming growth factor-beta 1 (TGF-beta 1), and basic fibroblast growth factor, which were colocalized in the collagenous matrix of the multilayer. The inclusion of 17 beta-estradiol (10(-11) to 10(-9) M) in the culture medium increased multilayer depths, increased labeling for IGF-I, IGF-II, and TGF-beta 1, and resulted in earlier detection of TGF-beta 1 label. In contrast, the increase in multilayer depth resulting from treatment with human platelets, an exogenous source of growth factors, was not accompanied by an increase in matrix IGF-I, IGF-II, or TGF-beta 1 label, suggesting a particular effect of estradiol to facilitate this process. Because growth factors in bone matrix may act as coupling agents when released during resorption, reduced growth factor incorporation in the presence of reduced sex steroid concentrations may lead to uncoupling of resorption and subsequent formation.

scholarly journals Mel1c Mediated Monochromatic Light-Stimulated IGF-I Synthesis through the Intracellular Gαq/PKC/ERK Signaling Pathway

2019 ◽  
Vol 20 (7) ◽  
pp. 1682
Author(s):  
Shujie Ning ◽  
Zixu Wang ◽  
Jing Cao ◽  
Yulan Dong ◽  
Yaoxing Chen
Keyword(s):  
Signaling Pathway ◽  
Intracellular Signaling ◽  
Monochromatic Light ◽  
Cyclic Adenosine Monophosphate ◽  
Adenosine Monophosphate ◽  
Erk Signaling ◽  
Sham Operation ◽  
Intracellular Signaling Pathway ◽  
Igf I

Previous studies have demonstrated that monochromatic light affects plasma melatonin (MEL) levels, which in turn regulates hepatic insulin-like growth factor I (IGF-I) secretion via the Mel1c receptor. However, the intracellular signaling pathway initiated by Mel1c remains unclear. In this study, newly hatched broilers, including intact, sham operation, and pinealectomy groups, were exposed to either white (WL), red (RL), green (GL), or blue (BL) light for 14 days. Experiments in vivo showed that GL significantly promoted plasma MEL formation, which was accompanied by an increase in the MEL receptor, Mel1c, as well as phosphorylated extracellular regulated protein kinases (p-ERK1/2), and IGF-I expression in the liver, compared to the other light-treated groups. In contrast, this GL stimulation was attenuated by pinealectomy. Exogenous MEL elevated the hepatocellular IGF-I level, which is consistent with increases in cyclic adenosine monophosphate (cAMP), Gαq, phosphorylated protein kinase C (p-PKC), and p-ERK1/2 expression. However, the Mel1c selective antagonist prazosin suppressed the MEL-induced expression of IGF-I, Gαq, p-PKC, and p-ERK1/2, while the cAMP concentration was barely affected. In addition, pretreatment with Ym254890 (a Gαq inhibitor), Go9863 (a PKC inhibitor), and PD98059 (an ERK1/2 inhibitor) markedly attenuated MEL-stimulated IGF-I expression and p-ERK1/2 activity. These results indicate that Mel1c mediates monochromatic GL-stimulated IGF-I synthesis through intracellular Gαq/PKC/ERK signaling.

Recombinant human insulin-like growth factor: testing the somatomedin hypothesis in hypophysectomized rats

1987 ◽  
Vol 112 (1) ◽  
pp. 123-132 ◽  
Author(s):  
A. Skottner ◽  
R. G. Clark ◽  
I. C. A. F. Robinson ◽  
L. Fryklund
Keyword(s):  
Growth Factor ◽  
Bone Growth ◽  
Body Weight Gain ◽  
Insulin Like Growth Factor ◽  
Recombinant Human Insulin ◽  
Poor Growth ◽  
Igf I ◽  
Hypophysectomized Rats ◽  
Growth Promoting

ABSTRACT The in-vivo biological activity of recombinant methionyl insulin-like growth factor I (met-IGF-I) was demonstrated in hypophysectomized rats by following blood glucose after an i.v. bolus injection of met-IGF-I; a dose-dependent decrease in blood sugar was seen. Membrane transport was studied using the non-metabolizable amino acid α-aminoisobutyric acid; stimulation was obtained with the highest dose used (90 μg/rat). To test the original somatomedin hypothesis, growth studies were performed in hypophysectomized rats. Two or three doses of met-IGF-I were given with three different administration regimes (i.v. or s.c. infusion, or s.c. injections twice daily) for 6 or 8 days. Little growth-promoting activity was observed, with a significant effect on body weight gain obtained only when met-IGF-I was given continuously at the highest dose used (180 μg/day). No effect was seen on the in-vivo uptake of radioactive sulphate into cartilage. Epiphyseal cartilage width increased slightly at the highest dose of met-IGF-I, but only when the hormone was given by infusion. When 180 μg met-IGF-I/day were given by injections, a significant effect on longitudinal bone growth was obtained (90 μm above control). The levels of IGF in the serum were not measurably increased after s.c. administration of met-IGF-I, whereas after i.v. infusion, significantly raised levels were obtained at the higher dose rates (3·0 ± 0·3 and 2·8 ± 0·1 units/ml). Growth hormone was much more effective than met-IGF-I even at 50-fold lower doses. Priming the animals with 10 mu. bovine GH/day followed by combined infusions of GH and met-IGF-I did not reveal any potentiating effects of met-IGF-I in the presence of GH. We conclude that met-IGF-I is a relatively poor growth-promoting agent when given systemically, and that somatomedins are more likely to act as local growth factors rather than as circulating mediators of the growth-promoting effects of GH. J. Endocr. (1987) 112, 123–132

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