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1.
The Actions of IGF-1 in the Growth Plate and Its Role in Postnatal Bone Elongation.
Racine, HL, Serrat, MA
Current osteoporosis reports. 2020;(3):210-227
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Abstract
PURPOSE OF REVIEW Bone elongation is a complex process driven by multiple intrinsic (hormones, growth factors) and extrinsic (nutrition, environment) variables. Bones grow in length by endochondral ossification in cartilaginous growth plates at ends of developing long bones. This review provides an updated overview of the important factors that influence this process. RECENT FINDINGS Insulin-like growth factor-1 (IGF-1) is the major hormone required for growth and a drug for treating pediatric skeletal disorders. Temperature is an underrecognized environmental variable that also impacts linear growth. This paper reviews the current state of knowledge regarding the interaction of IGF-1 and environmental factors on bone elongation. Understanding how internal and external variables regulate bone lengthening is essential for developing and improving treatments for an array of bone elongation disorders. Future studies may benefit from understanding how these unique relationships could offer realistic new approaches for increasing bone length in different growth-limiting conditions.
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A novel functional crosstalk between DDR1 and the IGF axis and its relevance for breast cancer.
Belfiore, A, Malaguarnera, R, Nicolosi, ML, Lappano, R, Ragusa, M, Morrione, A, Vella, V
Cell adhesion & migration. 2018;(4):305-314
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Abstract
In the last decades increasing importance has been attributed to the Insulin/Insulin-like Growth Factor signaling (IIGFs) in cancer development, progression and resistance to therapy. In fact, IIGFs is often deregulated in cancer. In particular, the mitogenic insulin receptor isoform A (IR-A) and the insulin-like growth factor receptor (IGF-1R) are frequently overexpressed in cancer together with their cognate ligands IGF-1 and IGF-2. Recently, we identified discoidin domain receptor 1 (DDR1) as a new IR-A interacting protein. DDR1, a non-integrin collagen tyrosine kinase receptor, is overexpressed in several malignancies and plays a role in cancer progression and metastasis. Herein, we review recent findings indicating that DDR1 is as a novel modulator of IR and IGF-1R expression and function. DDR1 functionally interacts with IR and IGF-1R and enhances the biological actions of insulin, IGF-1 and IGF-2. Conversely, DDR1 is upregulated by IGF-1, IGF-2 and insulin through the PI3K/AKT/miR-199a-5p circuit. Furthermore, we discuss the role of the non-canonical estrogen receptor GPER1 in the DDR1-IIGFs crosstalk. These data suggest a wider role of DDR1 as a regulator of cell response to hormones, growth factors, and signals coming from the extracellular matrix.
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Serum Insulin-Like Growth Factor Axis and the Risk of Pancreatic Cancer: Systematic Review and Meta-Analysis.
Gong, Y, Zhang, B, Liao, Y, Tang, Y, Mai, C, Chen, T, Tang, H
Nutrients. 2017;(4)
Abstract
OBJECTIVE To investigate the association between serum concentration of insulin-like growth factor (IGF) and the risk of pancreatic cancer (PaC). METHODS We identified eligible studies in Medline and EMBASE databases (no reference trials from 2014 to 2016) in addition to the reference lists of original studies and review articles on this topic. A summary of relative risks with 95% confidence intervals (CI) was calculated using a random-effects model. The heterogeneity between studies was assessed using Cochran Q and I² statistics. RESULTS Ten studies (seven nested case-control studies and three retrospective case-control studies) were selected as they met our inclusion criteria in this meta-analysis. All these studies were published between 1997 and 2013. The current data suggested that serum concentrations of IGF-I, IGF-II and insulin-like growth factor binding protein-3 (IGFBP-3)in addition to the IGF-I/IGFBP-3 ratio were not associated with an increased risk of PaC (Summary relative risks (SRRs) = 0.92, 95% CI: 0.67-1.16 for IGF-I; SRRs = 0.84, 95% CI: 0.54-1.15 for IGF-II; SRRs = 0.93, 95% CI: 0.69-1.17 for IGFBP-3; SRRs = 0.97, 95% CI: 0.71-1.23 for IGF-I/IGFBP-3 ratio). There was no publication bias in the present meta-analysis. CONCLUSION Serum concentrations of IGF-I, IGF-II, IGFBP-1 and IGFBP-3 as well as the IGF-I/IGFBP-3 ratio were not associated with increased risk of PaC.
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Recovery responses of testosterone, growth hormone, and IGF-1 after resistance exercise.
Kraemer, WJ, Ratamess, NA, Nindl, BC
Journal of applied physiology (Bethesda, Md. : 1985). 2017;(3):549-558
Abstract
The complexity and redundancy of the endocrine pathways during recovery related to anabolic function in the body belie an oversimplistic approach to its study. The purpose of this review is to examine the role of resistance exercise (RE) on the recovery responses of three major anabolic hormones, testosterone, growth hormone(s), and insulin-like growth factor 1. Each hormone has a complexity related to differential pathways of action as well as interactions with binding proteins and receptor interactions. Testosterone is the primary anabolic hormone, and its concentration changes during the recovery period depending on the upregulation or downregulation of the androgen receptor. Multiple tissues beyond skeletal muscle are targeted under hormonal control and play critical roles in metabolism and physiological function. Growth hormone (GH) demonstrates differential increases in recovery with RE based on the type of GH being assayed and workout being used. IGF-1 shows variable increases in recovery with RE and is intimately linked to a host of binding proteins that are essential to its integrative actions and mediating targeting effects. The RE stress is related to recruitment of muscle tissue with the glandular release of hormones as signals to target tissues to support homeostatic mechanisms for metabolism and tissue repair during the recovery process. Anabolic hormones play a crucial role in the body's response to metabolism, repair, and adaptive capabilities especially in response to anabolic-type RE. Changes of these hormones following RE during recovery in the circulatory biocompartment of blood are reflective of the many mechanisms of action that are in play in the repair and recovery process.
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IGF-I in the clinics: Use in retinopathy of prematurity.
Hellström, A, Ley, D, Hansen-Pupp, I, Hallberg, B, Ramenghi, LA, Löfqvist, C, Smith, LE, Hård, AL
Growth hormone & IGF research : official journal of the Growth Hormone Research Society and the International IGF Research Society. 2016;:75-80
Abstract
Retinopathy of prematurity is a potentially blinding disease, which is associated with low neonatal IGF-I serum concentrations and poor growth. In severe cases impaired retinal vessel growth is followed by pathologic neovascularization, which may lead to retinal detachment. IGF-I may promote growth even in catabolic states. Treating preterm infants with recombinant human (rh) IGF-I to concentrations normally found during gestation has been suggested to have a preventative effect on ROP. A recent phase 2 study treating infants (gestational age between 23weeks+0days and 27weeks +6days) with rhIGF-I/IGF binding protein-3 until 30 postmenstrual weeks showed no effect on ROP but a 53% reduction in severe bronchopulmonary dysplasia and 44% reduction in severe intraventricular hemorrhage. Oxygen is a major risk factor for ROP and during the phase 2 study oxygen saturation targets were increased to 90-95%, due to national guidelines, which might have affected ROP rate and severity making increased IGF-I a weaker preventative factor for ROP.
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Insulin-Like Growth Factor-I is a Marker for the Nutritional State.
Hawkes, CP, Grimberg, A
Pediatric endocrinology reviews : PER. 2015;(2):499-511
Abstract
Measurement of the serum concentration of insulin-like growth factor-I (IGF-l) is generally used as a screening investigation for disorders of the growth hormone (GH)/IGF-I axis in children and adolescents with short stature. IGF-I concentration is sensitive to short-term and chronic alterations in the nutritional state, and the interpretation of IGF-I measurements requires knowledge of the child's nutritional status. In this review, we summarize the effects of nutrition on the GH/IGF-I axis, and review the clinical implications of these interactions throughout childhood, both in under-nutrition and over-nutrition.
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In search of antiaging modalities: evaluation of mTOR- and ROS/DNA damage-signaling by cytometry.
Darzynkiewicz, Z, Zhao, H, Halicka, HD, Li, J, Lee, YS, Hsieh, TC, Wu, JM
Cytometry. Part A : the journal of the International Society for Analytical Cytology. 2014;(5):386-99
Abstract
This review presents the evidence in support of the IGF-1/mTOR/S6K1 signaling as the primary factor contributing to aging and cellular senescence. Reviewed are also specific interactions between mTOR/S6K1 and ROS-DNA damage signaling pathways. Outlined are critical sites along these pathways, including autophagy, as targets for potential antiaging (gero-suppressive) and/or chemopreventive agents. Presented are applications of flow- and laser scanning- cytometry utilizing phospho-specific Abs, to monitor activation along these pathways in response to the reported antiaging drugs rapamycin, metformin, berberine, resveratrol, vitamin D3, 2-deoxyglucose, and acetylsalicylic acid. Specifically, effectiveness of these agents to attenuate the level of constitutive mTOR signaling was tested by cytometry and confirmed by Western blotting through measuring phosphorylation of the mTOR-downstream targets including ribosomal protein S6. The ratiometric analysis of phosphorylated to total protein along the mTOR pathway offers a useful parameter reporting the effects of gero-suppressive agents. In parallel, their ability to suppress the level of constitutive DNA damage signaling induced by endogenous ROS was measured. While the primary target of each of these agents may be different the data obtained on several human cancer cell lines, WI-38 fibroblasts and normal lymphocytes suggest common downstream mechanism in which the decline in mTOR/S6K1 signaling and translation rate is coupled with a reduction of oxidative phosphorylation and ROS that leads to decreased oxidative DNA damage. The combined assessment of constitutive γH2AX expression, mitochondrial activity (ROS, ΔΨm), and mTOR signaling provides an adequate gamut of cell responses to test effectiveness of gero-suppressive agents. Described is also an in vitro model of induction of cellular senescence by persistent replication stress, its quantitative analysis by laser scanning cytometry, and application to detect the property of the studied agents to attenuate the induction of senescence. Discussed is cytometric analysis of cell size and heterogeneity of size as a potential biomarker used to asses gero-suppressive agents and longevity.
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Algorithms for the prediction of retinopathy of prematurity based on postnatal weight gain.
Binenbaum, G
Clinics in perinatology. 2013;(2):261-70
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Abstract
Current ROP screening guidelines represent a simple risk model with two dichotomized factors, birth weight and gestational age at birth. Pioneering work has shown that tracking postnatal weight gain, a surrogate for low insulin-like growth factor 1, may capture the influence of many other ROP risk factors and improve risk prediction. Models including weight gain, such as WINROP, ROPScore, and CHOP ROP, have demonstrated accurate ROP risk assessment and a potentially large reduction in ROP examinations, compared to current guidelines. However, there is a need for larger studies, and generalizability is limited in countries with developing neonatal care systems.
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Regulation of cardiac autophagy by insulin-like growth factor 1.
Troncoso, R, Díaz-Elizondo, J, Espinoza, SP, Navarro-Marquez, MF, Oyarzún, AP, Riquelme, JA, Garcia-Carvajal, I, Díaz-Araya, G, García, L, Hill, JA, et al
IUBMB life. 2013;(7):593-601
Abstract
Insulin-like growth factor-1 (IGF-1) signaling is a key pathway in the control of cell growth and survival. Three critical nodes in the IGF-1 signaling pathway have been described in cardiomyocytes: protein kinase Akt/mammalian target of rapamycin (mTOR), Ras/Raf/extracellular signal-regulated kinase (ERK), and phospholipase C (PLC)/inositol 1,4,5-triphosphate (InsP3 )/Ca(2+) . The Akt/mTOR and Ras/Raf/ERK signaling arms govern survival in the settings of cardiac stress and hypertrophic growth. By contrast, PLC/InsP3 /Ca(2+) functions to regulate metabolic adaptability and gene transcription. Autophagy is a catabolic process involved in protein degradation, organelle turnover, and nonselective breakdown of cytoplasmic components during nutrient starvation or stress. In the heart, autophagy is observed in a variety of human pathologies, where it can be either adaptive or maladaptive, depending on the context. We proposed the hypothesis that IGF-1 protects the heart by rescuing the mitochondrial metabolism and the energetics state, reducing cell death and controls the potentially exacerbate autophagic response to nutritional stress. In light of the importance of IGF-1 and autophagy in the heart, we review here IGF-1 signaling and autophagy regulation in the context of cardiomyocyte nutritional stress.
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IGF-1, the cross road of the nutritional, inflammatory and hormonal pathways to frailty.
Maggio, M, De Vita, F, Lauretani, F, Buttò, V, Bondi, G, Cattabiani, C, Nouvenne, A, Meschi, T, Dall'Aglio, E, Ceda, GP
Nutrients. 2013;(10):4184-205
Abstract
The decline in functional capacity is a heterogeneous phenomenon in the elderly. An accelerated ageing determines a frail status. It results in an increased vulnerability to stressors for decreased physiological reserves. The early identification of a frail status is essential for preventing loss of functional capacity, and its clinical consequences. Frailty and mobility limitation result from an interplay of different pathways including multiple anabolic deficiency, inflammation, oxidative stress, and a poor nutritional status. However, the age-related decline in insulin-like growth factor 1 (IGF-1) bioactivity deserves special attention as it could represent the ideal crossroad of endocrine, inflammatory, and nutritional pathways to frailty. Several minerals, namely magnesium, selenium, and zinc, appear to be important determinants of IGF-1 bioactivity. This review aims to provide an overview of the potential usefulness of nutrients modulating IGF-1 as potential therapeutic targets in the prevention of mobility limitation occurring in frail older subjects.