RESUMEN
STAT5B deficiency, a rare autosomal recessive disorder characterized by severe growth hormone insensitivity (GHI) and immunodeficiency, can manifest as fatal pulmonary complications. We describe atypical STAT5B deficiency associated with a novel homozygous frame-shift STAT5B variant [c.1453delG, p.(Asp485Thrfs*29)] identified in a young 17.6 yr old female subject who had severe postnatal growth impairment, biochemistries typical of GHI, an immune profile notable for hypergammaglobulinaemia and elevated B lymphocytes, and lack of pulmonary disease. Marked elevation of serum prolactin and pathologically diagnosed eczema were evident. In reconstitution studies, the STAT5B p.(Asp485Thrfs*29) was expressed although expression was reduced compared to wild-type STAT5B and a previously identified STAT5B p.(Gln368Profs*9) variant. Both truncated STAT5B peptides could not be activated by GH, nor mobilize to the nucleus. We conclude that an intact, functional, STAT5B is essential for normal GH-mediated growth, while expressed loss-of-function STAT5B variants may alleviate severe immune and pulmonary issues normally associated with STAT5B deficiency.
Asunto(s)
Enanismo , Síndromes de Inmunodeficiencia , Femenino , Humanos , Factor I del Crecimiento Similar a la Insulina/metabolismo , Factor de Transcripción STAT5/genética , Factor de Transcripción STAT5/metabolismo , Enanismo/genética , Síndromes de Inmunodeficiencia/genética , Hormona del Crecimiento/metabolismoRESUMEN
Mucopolysaccharidoses (MPSs) are multiorgan devastating diseases for which hematopoietic cell transplantation (HCT) and, to a lesser extent, enzyme replacement therapy have substantially altered the course of the disease. Furthermore, they have resulted in increased overall survival, especially for Hurler disease (MPS-1). However, despite the identification of clinical predictors and harmonized transplantation protocols, disease progression still poses a significant burden to patients, although at a slower pace. To design better therapies, we need to understand why and where current therapies fail. In this review, we discuss important aspects of the underlying disease and the disease progression. We note that the majority of progressive symptoms that occur in "hard-to-treat" tissues are actually tissues that are difficult to reach, such as avascular connective tissue or tissues isolated from the circulation by a specific barrier (eg, blood-brain barrier, blood-retina barrier). Although easily reached tissues are effectively cured by HCT, disease progression is observed in these "hard-to-reach" tissues. We used these insights to critically appraise ongoing experimental endeavors with regard to their potential to overcome the encountered hurdles and improve long-term clinical outcomes in MPS patients treated with HCT.
Asunto(s)
Trasplante de Células Madre Hematopoyéticas , Mucopolisacaridosis , Mucopolisacaridosis I , Barrera Hematoencefálica , Terapia de Reemplazo Enzimático , Humanos , Mucopolisacaridosis I/terapiaRESUMEN
Insulin-like growth factor (IGF)-II is considered to function as an important fetal growth factor, which is structurally and functionally related to IGF-I and proinsulin. At least in vitro, IGF-II actions are mediated through the IGF-I receptor and to a lesser extent the insulin receptor. After birth, the function of IGF-II is less clear although in adults the serum level of IGF-II exceeds that of IGF-I several fold. The IGF-II gene is maternally imprinted, with exception of the liver and several parts of the brain, where it is expressed from both alleles. The regulation, organization, and translation of the IGF-II gene is complex, with five different putative promotors leading to a range of noncoding and coding mRNAs. The 180-amino acid pre-pro-IGF-II translation product can be divided into five domains and include a N-terminal signal peptide of 24 amino acid residues, the 67 amino acid long mature protein, and an 89 residues extension at the COOH terminus, designated as the E-domain. After removal of the signal peptide, the processing of pro-IGF-II into mature IGF-II requires various steps including glycosylation of the E-domain followed by the action of endo-proteases. Several of these processing intermediates can be found in the human circulation. There is increasing evidence that, besides IGF-II, several incompletely processed precursor forms of the protein, and even a 34-amino acid peptide (preptin) derived from the E-domain of pro-IGF-II, exhibit distinct biological activities. This review will focus on the current insights regarding the specific roles of the latter proteins in cancer, glucose homeostasis, and bone physiology. To address this topic clearly in the right context, a concise overview of the biological and biochemical properties of IGF-II and several relevant aspects of the IGF system will be provided.
Asunto(s)
Hepatitis C/genética , Hipoglucemia/genética , Factor II del Crecimiento Similar a la Insulina/genética , Neoplasias/genética , Osteosclerosis/genética , Fragmentos de Péptidos/genética , Precursores de Proteínas/genética , Regulación de la Expresión Génica , Glucosa/metabolismo , Hepatitis C/complicaciones , Hepatitis C/metabolismo , Hepatitis C/patología , Homeostasis/genética , Humanos , Hipoglucemia/metabolismo , Hipoglucemia/patología , Factor I del Crecimiento Similar a la Insulina/genética , Factor I del Crecimiento Similar a la Insulina/metabolismo , Factor II del Crecimiento Similar a la Insulina/química , Factor II del Crecimiento Similar a la Insulina/metabolismo , Neoplasias/metabolismo , Neoplasias/patología , Osteogénesis/genética , Osteosclerosis/complicaciones , Osteosclerosis/metabolismo , Osteosclerosis/patología , Fragmentos de Péptidos/química , Fragmentos de Péptidos/metabolismo , Regiones Promotoras Genéticas , Dominios Proteicos , Precursores de Proteínas/química , Precursores de Proteínas/metabolismo , Receptor IGF Tipo 1/genética , Receptor IGF Tipo 1/metabolismo , Receptor de Insulina/genética , Receptor de Insulina/metabolismo , Transducción de SeñalRESUMEN
Corneal clouding, causing visual impairment, is seen in nearly all patients with mucopolysaccharidosis type 1 (MPS-1). Hematopoietic cell transplantation (HCT) is able to stabilize disease in many organs. Residual disease in several tissues is being increasingly recognized, however. Data on the effect of HCT on ocular disease in patients with MPS-1 are contradictory. With this study, we aim to clarify the long-term effects of HCT on ocular disease in these patients. Best corrected visual acuity (BCVA), refraction, intraocular pressure (IOP), and slit-lamp biomicroscopic and fundoscopic examinations, including corneal clouding, were collected prospectively from 24 patients with MPS-1 who underwent HCT successfully between 2003 and 2018 (92% with >95% chimerism and normal enzyme activity after HCT). The course of corneal clouding and BCVA after HCT were analyzed using a linear mixed model. Other parameters studied were clinical phenotype, age at time of transplantation, and hematologic enzyme activity after transplantation. Outcomes of additional ophthalmologic tests were described. In addition, IDUA and α-galactosidase A (AGAL) enzyme activity and glycosaminoglycan (GAG) concentration in tear fluid were determined. Corneal clouding stabilized in the first years after HCT but increased rapidly beyond 3 years (P < .0001). BCVA and IOP also worsened over time (P = .01 and P < .0001, respectively). IDUA activity in tear fluid remained very low (P < .0001). After initial stabilization in the cornea, ongoing ocular disease and low IDUA activity in tear fluid is seen in patients with MPS-1 despite treatment with HCT, unveiling a weak spot of current standard therapy. New therapies that overcome these shortcomings are needed to improve the late outcomes of patients.
Asunto(s)
Trasplante de Células Madre Hematopoyéticas , Mucopolisacaridosis I , Niño , Córnea , Humanos , Presión Intraocular , Mucopolisacaridosis I/terapia , FenotipoRESUMEN
BACKGROUND: The reason for the insufficient catch-up growth seen in 10% of children born small for gestational age (SGA) is poorly understood. Disturbances in the growth hormone (GH) - insulin-like growth factor (IGF) axis might underlie this failure to show sufficient catch-up growth. CONCLUSION: This review summarizes insights gained in the molecular and (epi) genetic mechanisms of the GH-IGF axis in short children born SGA. The most notable anomalies of the IGF system are the lowered IGF-I levels in both cord blood and the placenta, and the increased expression of IGF-binding proteins (IGFBP)-1 and IGFBP-2, which inhibit IGF-I, in the placenta of SGA neonates. These observations suggest a decreased bioactivity of IGF-I in utero. IGF-I levels remain reduced in SGA children with short stature, as well as IGFBP-3 and acid-labile subunit levels. Proteolysis of IGFBP-3 appears to be increased.
Asunto(s)
Epigénesis Genética , Hormona de Crecimiento Humana , Recién Nacido Pequeño para la Edad Gestacional/metabolismo , Proteínas de Unión a Factor de Crecimiento Similar a la Insulina , Factor I del Crecimiento Similar a la Insulina , Proteolisis , Niño , Femenino , Hormona de Crecimiento Humana/genética , Hormona de Crecimiento Humana/metabolismo , Humanos , Recién Nacido , Proteínas de Unión a Factor de Crecimiento Similar a la Insulina/genética , Proteínas de Unión a Factor de Crecimiento Similar a la Insulina/metabolismo , Factor I del Crecimiento Similar a la Insulina/genética , Factor I del Crecimiento Similar a la Insulina/metabolismo , MasculinoRESUMEN
Although disease progression in mucopolysaccharidosis type I (MPS-I) can be attenuated by hematopoietic cell transplantation (HCT), it is increasingly recognized that residual disease is substantial. Biomarkers that would allow us to evaluate the efficacy of HCT (and upcoming new therapies) in nonhematologic tissues are needed. Current biomarkers, including the iduronidase (IDUA) activity in leukocytes, are not suitable for this purpose because they are assessed in tissues of hematologic origin and may not reflect enzyme availability in nonhematologic tissues. Saliva is a nonhematologic body fluid that can be collected easily and noninvasively. We hypothesized that the extent of recovery of IDUA activity in saliva after HCT could provide a better understanding of the penetration of donor-derived enzyme into nonhematologic compartments. This study in 20 patients with MPS-I shows that the measurement of IDUA activity in saliva is possible and allows diagnosis of IDUA deficiency (P < .0001), with values a magnitude further deviating from the normal range than when assayed in corresponding dried blood spots (DBSs). Furthermore, it could possibly differentiate between phenotypes (P = .045). More importantly, patients exhibit strikingly low values of IDUA in saliva after HCT, far below the normal range of control subjects (P = .013), contrasting the normal IDUA levels in DBSs. We postulate that the limited recovery of donor-derived IDUA activity in saliva after treatment reflects the situation in poorly responding nonhematologic tissue compartments, unveiling enzyme delivery as a weak spot of the current therapy. Salivary IDUA activity could be used as a biomarker for the evaluation of the effect of new therapies in well-vascularized nonhematologic tissues.
Asunto(s)
Biomarcadores/metabolismo , Iduronidasa/metabolismo , Mucopolisacaridosis I/diagnóstico , Mucopolisacaridosis I/terapia , Saliva/química , Biomarcadores/análisis , Preescolar , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Mucopolisacaridosis I/patologíaRESUMEN
OBJECTIVE: Acid-labile subunit (ALS) deficiency (ACLSD), caused by homozygous or compound heterozygous IGFALS mutations, is associated with moderate short stature, delayed puberty, low serum IGF-I and ALS and extremely low serum IGFBP-3. Its effect on birth weight, head circumference, bone mineral density (BMD), serum IGF-II and IGFBP-2 is uncertain, as well as the phenotype of heterozygous carriers of IGFALS mutations (partial ACLSD). DESIGN: From all available members of five Turkish families, carrying three mutations in exon 2 of IGFALS (c.1462G > A, p.Asp488Asn (families A, B, E); c.251A > G, p.Asn84Ser (families C and E) and c.1477del, p.Arg493fs (family D)), clinical, laboratory and BMD data were collected. METHODS: Auxological and biochemical findings were expressed as SDS for age and gender. Ternary complex formation in serum was investigated by size-exclusion chromatography. BMD using DXA bone densitometry was adjusted for height and age (Ha-BMD z-score). RESULTS: In ACLSD (n = 24), mean ± s.d. height SDS (-2.7 ± 1.2), head circumference SDS (-2.3 ± 0.5) and body mass index (BMI) (-0.6 ± 1.0 SDS) were lower than those in partial ACLSD (n = 26, P ≤ 0.01) and birth weight SDS (n = 7) tended to be lower (-2.2 ± 1.1 vs -0.6 ± 0.3 in partial ACLSD (P = 0.07)). Serum IGF-I was -3.7 ± 1.4 vs -1.0 ± 1.0, IGF-II: -5.6 ± 0.7 vs -1.3 ± 0.7, ALS: <-4.4 ± 1.2 vs -2.1 ± 0.9 and IGFBP-3: -9.0 ± 1.9 vs -1.6 ± 0.8 SDS respectively (P < 0.001). Ha-BMD z-score was similar and normal in both groups. CONCLUSIONS: To the known phenotype of ACLSD (i.e. short stature, reduced serum levels of IGF-I and ALS, extremely low serum IGFBP-3 and disturbed ternary complex formation), we add reduced birth weight, head circumference and serum IGF-II.
Asunto(s)
Densidad Ósea/genética , Proteínas Portadoras/genética , Glicoproteínas/genética , Trastornos del Crecimiento/genética , Proteína 3 de Unión a Factor de Crecimiento Similar a la Insulina/metabolismo , Factor II del Crecimiento Similar a la Insulina/metabolismo , Factor I del Crecimiento Similar a la Insulina/metabolismo , Absorciometría de Fotón , Adolescente , Peso al Nacer/genética , Índice de Masa Corporal , Proteínas Portadoras/metabolismo , Cefalometría , Niño , Femenino , Glicoproteínas/metabolismo , Trastornos del Crecimiento/diagnóstico por imagen , Trastornos del Crecimiento/metabolismo , Heterocigoto , Homocigoto , Humanos , Masculino , Mutación , Fenotipo , Pubertad Tardía/genética , Pubertad Tardía/metabolismo , TurquíaRESUMEN
The syndrome of nonislet cell tumor induced hypoglycemia (NICTH) represent extreme cases of excessive expression and production of incompletely processed high-molecular-mass pro-IGF-II forms (big IGF-II) by an often large tumor. Tumor-derived big IGF-II is responsible for enhanced insulin-like effects in the body through complicated mechanisms, leading to hypoglycemia. Case studies on NICTH usually focus on measurements of diagnostic parameters in the circulation of patients. Some studies have also reported on qualitative immunohistochemical analysis of tumor tissue, in particular with respect to the expression of IGF-II at the mRNA or protein level. However, quantitative data on the concentrations of IGFs and IGFBPs in tumor specimen causing NICTH, in relation to their corresponding plasma levels are lacking. Such an analysis would provide an estimate of the total potential of (big) IGF-II retained by the tumor and more insight in the relative levels of different IGFBPs and their origin in the circulation, that is, systemically induced by tumor related factors or directly tumor-derived. Here we investigated quantitatively the levels of IGFs and IGFBPs in a large, 1.76 kg weighing, solitary fibrous tumor from a typical case of NICTH using highly specific immunometric assays. Besides a high level of big IGF-II, patient's plasma also contained increased levels of both IGFBP-2 and -6 which declined after removal of the tumor. These IGFBPs have a higher affinity for (pro-) IGF-II than IGF-I and exhibit intrinsic IGF-independent bioactivities. Tumor tissue contained high amounts of big IGF-II and IGFBP-6, exceeding that in patient's circulation many-fold. A relatively low tumor content of IGFBP-2 was found suggesting that the preoperative high levels in plasma were attributable to systemic mechanisms. The background literature and possible implications of these findings are briefly discussed. Based on the present results we postulate that tumor tissue is not the source of the elevated levels of IGFBP-2 often seen in NICTH patients. Large tumors that cause NICTH can produce IGFBP-6 leading to enhanced levels of this IGFBP in the circulation. Hence, the measurement of IGFBP-6 in plasma may serve as an additional marker of this disease pattern.
Asunto(s)
Neoplasias Abdominales/genética , Tumores de Células Gigantes/genética , Hipoglucemia/genética , Proteína 2 de Unión a Factor de Crecimiento Similar a la Insulina/sangre , Proteína 6 de Unión a Factor de Crecimiento Similar a la Insulina/sangre , Neoplasias Abdominales/complicaciones , Neoplasias Abdominales/patología , Neoplasias Abdominales/cirugía , Regulación de la Expresión Génica , Tumores de Células Gigantes/complicaciones , Tumores de Células Gigantes/patología , Tumores de Células Gigantes/cirugía , Humanos , Hipoglucemia/complicaciones , Hipoglucemia/patología , Hipoglucemia/cirugía , Proteína 2 de Unión a Factor de Crecimiento Similar a la Insulina/genética , Proteína 6 de Unión a Factor de Crecimiento Similar a la Insulina/genética , Factor I del Crecimiento Similar a la Insulina/genética , Factor I del Crecimiento Similar a la Insulina/metabolismo , Factor II del Crecimiento Similar a la Insulina/genética , Factor II del Crecimiento Similar a la Insulina/metabolismo , Masculino , Persona de Mediana Edad , Precursores de Proteínas/genética , Precursores de Proteínas/metabolismo , Transducción de Señal , Técnicas de Cultivo de TejidosRESUMEN
Extracellular vesicles, in particular exosomes, have gained much attention as potent mediators of intercellular signaling. Exosomes are 50-130 nm intraluminal vesicles of multivesicular bodies (MVB) that are secreted into the extracellular environment upon fusion of MVB with the plasma membrane. Current research on exosomes focuses on their biogenesis, including specific sorting mechanisms, their potential to transfer proteins and RNA from their cells of origin to target cells, specific methods of vesicle isolation, and their possible application as diagnostic and therapeutic devices. Exosomes are vesicles of endocytic origin that contain a portion of the cytoplasm. Their molecular components represent the composition and thereby the physiological state of the cells from which they originate. In this review, we recapitulate the discovery of exosomes and the subsequent expansion of exosome research into a variety of different areas of interest, with a specific focus on how exosomes could prove to be invaluable for both diagnostic and therapeutic applications within the research field of inborn errors of metabolism.
Asunto(s)
Exosomas/fisiología , Errores Innatos del Metabolismo/diagnóstico , Errores Innatos del Metabolismo/terapia , Animales , Transporte Biológico , Biomarcadores/metabolismo , Sistemas de Liberación de Medicamentos/métodos , HumanosRESUMEN
Lactic acidosis is a rare complication of haematological malignancies with a poor prognostic outcome and unclear aetiology. Possible mechanisms include high rate of glycolysis by cancer cells, in part due to over-expression of hexokinase II. The insulin-like growth factor (IGF)-system has an important role in normal as well as tumour cell growth. We present a case of a 79-year-old man with a diffuse large B-cell lymphoma and lactic acidosis. Initially, the patient was successfully treated according to the R-CHOP scheme. After recurrence of disease, the patient was treated according to a protocol of the Dutch-Belgian Haemato-Oncology Group (HOVON-85 study). Eleven months after completion of the last therapy, the patient still appeared to be in complete remission. Serum levels of IGFs, pro-IGF-IIE[68-88], IGF binding proteins (IGFBPs)-1 to -4, acid labile subunit (ALS), as well as ternary IGF-I-IGFBP-3-ALS complex formation, were determined in samples taken before, during and after treatment, respectively. Before treatment patient's serum concentration of the growth hormone-dependent parameters of the IGF-system and IGF-II were clearly reduced when compared with patient's values during remission of disease. On the other hand, during acidosis a relatively higher proportion of IGFs is present in binary complexes, instead of 150 kDa complexes, that may allow an increased access of IGFs to target cells including the malignant ones. Pretreatment serum levels of IGFBP-1 and -2 were elevated, decreased during therapy and normalized at remission. Especially IGFBP-2 seems a suitable marker for disease activity.
Asunto(s)
Acidosis Láctica/complicaciones , Linfoma de Células B Grandes Difuso/sangre , Linfoma de Células B Grandes Difuso/complicaciones , Somatomedinas/metabolismo , Anciano , Humanos , Linfoma de Células B Grandes Difuso/terapia , MasculinoRESUMEN
New treatment targets need to be identified in gastrointestinal stromal tumors (GISTs) to extend the treatment options for patients experiencing failure with small-molecule tyrosine kinase inhibitors, such as imatinib. Insulin-like growth factor (IGF)-II acts as an autocrine factor in several tumor types by binding to IGF receptor type 1 (IGF-1R) and/or the insulin receptor (IR) isoform A. The aim of the present study was to investigate the putative role of unprocessed pro-IGF-II, called 'big'-IGF-II, in GISTs. The imatinib-sensitive GIST882 and imatinib-resistant GIST48 cell lines secrete high levels of big-IGF-II as demonstrated by ELISA and Western blotting analyses. IR isoform A mRNA and protein expression, but not that of IGF-1R, was found in these KIT mutant cell lines and in KIT and platelet-derived growth factor receptor α-mutant GIST specimens. Down-regulation of either big-IGF-II or IR affected AKT and MAPK signaling and reduced survival in both cell lines. Disruption of big-IGF-II signaling in combination with imatinib had additive cytotoxic effects on GIST882 cells. IGF-II mRNA as determined by in situ hybridization was present in 91% of 60 primary GISTs. Immunohistochemical analysis of big-IGF-II protein expression was associated with moderate- to high-risk tumors compared with tumors with a lower risk classification (P < 0.028). Our data put forth the big-IGF-II/IR isoform A axis as an autocrine survival pathway and potential therapeutic target in GISTs.
Asunto(s)
Tumores del Estroma Gastrointestinal/fisiopatología , Factor II del Crecimiento Similar a la Insulina/fisiología , Precursores de Proteínas/fisiología , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/farmacología , Comunicación Autocrina/efectos de los fármacos , Comunicación Autocrina/fisiología , Benzamidas , Muerte Celular/efectos de los fármacos , Muerte Celular/fisiología , Supervivencia Celular/fisiología , Regulación hacia Abajo/fisiología , Femenino , Tumores del Estroma Gastrointestinal/metabolismo , Tumores del Estroma Gastrointestinal/patología , Humanos , Mesilato de Imatinib , Factor II del Crecimiento Similar a la Insulina/metabolismo , Masculino , Persona de Mediana Edad , Proteínas de Neoplasias/metabolismo , Piperazinas/farmacología , Precursores de Proteínas/metabolismo , Pirimidinas/farmacología , Receptor IGF Tipo 1/metabolismo , Receptor de Insulina/metabolismo , Células Tumorales Cultivadas , Adulto JovenRESUMEN
BACKGROUND: Estrogen deficiency induced by aromatase inhibitors may be a novel treatment modality for growth enhancement in short children, but may have adverse effects on bone, brain and reproduction. AIM: To assess growth effects and potential adverse effects of aromatase inhibition in male rats. METHODS: 26-day-old prepubertal rats received intramuscular injections with placebo or the aromatase inhibitor exemestane at a dose of 10, 30 or 100 mg/kg/week [E10, E30, E100(6)] for 6 weeks, completely covering the sexual maturation phase, or with 3 weeks E100 followed by 3 weeks placebo [E100(3)]. Growth parameters and histology of the testis, seminal vesicle and brain were analyzed. Bone architecture was studied with X-ray microtomography. RESULTS: Exemestane dose-dependently decreased body weight and tail length gain, as well as liver and seminal vesicle weights, but did not affect nose-anus length gain, growth plate width or radial growth. E100(6) decreased trabecular thickness (epiphysis and metaphysis) and number (metaphysis). Normal IGF-I levels and brain, testis and seminal vesicle morphology were observed. E100(3) resulted in decreased tail length gain only. CONCLUSION: Exemestane treatment during sexual maturation did not augment linear growth in male rats, but caused impaired body weight and tail length gain and osteopenia.
Asunto(s)
Androstadienos/efectos adversos , Inhibidores de la Aromatasa/efectos adversos , Densidad Ósea/efectos de los fármacos , Enfermedades Óseas Metabólicas/inducido químicamente , Huesos/efectos de los fármacos , Cola (estructura animal)/crecimiento & desarrollo , Animales , Inhibidores de la Aromatasa/farmacología , Peso Corporal/efectos de los fármacos , Placa de Crecimiento/efectos de los fármacos , Masculino , Ratas , Ratas Wistar , Cola (estructura animal)/efectos de los fármacos , Microtomografía por Rayos XRESUMEN
BACKGROUND: Aromatase inhibition has been proposed as a potential approach for growth enhancement in children with short stature, but detailed animal studies are lacking. AIM: To assess the effect and potential adverse effects of aromatase inhibition on growth in female rats. METHODS: Prepubertal Wistar rats received intramuscular injections with placebo or the aromatase inhibitor exemestane at a dose of 10, 30 or 100 mg/kg/week (E10, E30, E100) for 3 weeks. A control group was ovariectomized (OVX). Weight and length gain, tibia and femur length, growth plate width, organ weights, insulin-like growth factor I (IGF-I) levels, and histology of the ovaries, uterus and brain were analyzed. X-ray microtomography of femora was performed. RESULTS: E100 significantly increased weight gain and growth plate width, but less prominently than OVX. Trabecular number and thickness were decreased in E100 and OVX in the metaphysis and epiphysis. E100 significantly decreased ovarian weight and multiple cysts were seen upon histological evaluation. No significant effects were found on IGF-I levels and brain morphology in E100. E10 and E30 had no effects on growth. CONCLUSION: A high dose of exemestane marginally increases axial and appendicular growth in female rats, at the expense of osteopenia and polycystic ovaries.
Asunto(s)
Androstadienos/farmacología , Densidad Ósea/efectos de los fármacos , Crecimiento y Desarrollo/efectos de los fármacos , Quistes Ováricos/inducido químicamente , Maduración Sexual/efectos de los fármacos , Androstadienos/administración & dosificación , Animales , Inhibidores de la Aromatasa/administración & dosificación , Inhibidores de la Aromatasa/farmacología , Evaluación Preclínica de Medicamentos , Femenino , Inyecciones Intramusculares , Quistes Ováricos/fisiopatología , Placebos , Control de Calidad , Ratas , Ratas Wistar , Maduración Sexual/fisiología , Regulación hacia Arriba/efectos de los fármacos , Microtomografía por Rayos XRESUMEN
BACKGROUND: IGF binding protein (IGFBP)-2 might protect against cardiovascular disease. Small for gestational age (SGA) birth could be associated with a higher risk for type 2 diabetes mellitus and cardiovascular disease in later life. No data are available on the relationship between serum IGFBP-2 levels and cardiovascular risk factors in young adults and children born SGA. OBJECTIVE: The aim of the study was to determine circulating IGFBP-2 levels in subjects born SGA and to investigate the association with cardiovascular risk factors. METHODS: IGFBP-2 levels were measured in sera from 151 young adults born SGA and 147 short SGA children. Age- and gender-adjusted sd scores (SDS) were calculated. We determined blood pressure, serum lipids, body composition by dual-energy x-ray absorptiometry, and glucose homeostasis by homeostasis model of assessment for insulin resistance or frequently sampled iv glucose tolerance test. RESULTS: Serum IGFBP-2 SDS was significantly reduced in SGA young adults (with normal or short stature). Fat mass SDS was relatively high in SGA young adults and was reduced in short SGA children. Serum IGFBP-2 SDS in SGA young adults correlated positively with insulin sensitivity and negatively with fat mass SDS, insulin secretion (acute insulin response), fasting insulin, homeostasis model of assessment for insulin resistance, total cholesterol, triglycerides, and blood pressure SDS. The association between serum IGFBP-2 SDS and insulin sensitivity, blood pressure, total cholesterol, and triglyceride levels persisted after adjustment for known covariates including fat mass SDS. In short SGA children, IGFBP-2 SDS did not correlate with any of the cardiovascular risk factors. CONCLUSION: In young adults who were born SGA, serum IGFBP-2 levels associate with cardiovascular risk markers.
Asunto(s)
Enfermedades Cardiovasculares/etiología , Recién Nacido Pequeño para la Edad Gestacional , Proteína 2 de Unión a Factor de Crecimiento Similar a la Insulina/sangre , Tejido Adiposo/metabolismo , Adulto , Niño , Femenino , Humanos , Recién Nacido , Resistencia a la Insulina , Lípidos/sangre , Masculino , Factores de Riesgo , Adulto JovenRESUMEN
CONTEXT: IGF binding protein (IGFBP)-1 is the only acute regulator of IGF-I bioavailability. Its production is suppressed by insulin, and low levels are associated with hyperinsulinemia and cardiovascular disease risk in adults. Data on IGFBP-1 levels in short, small for gestational age (SGA) subjects are scarce, and associations with IGFBP1 promoter single nucleotide polymorphisms have not been established. OBJECTIVE: The aim of the study was to determine IGFBP-1 levels in short SGA subjects compared with those in controls, to assess genotype frequency of the -575 G/A single nucleotide polymorphism, and to determine its impact on IGFBP-1 levels. SUBJECTS: A total of 272 short subjects born SGA and 330 subjects with normal stature (245 children, 85 young adults) participated in the study. OUTCOME MEASURES: We measured fasting levels of IGFBP-1, IGF-I, insulin and lipid parameters, and body composition. RESULTS: IGFBP-1 sd score (SDS) was comparable to controls in lean, short, SGA children but significantly lower in short SGA adults with normal fat mass (P < 0.001). IGFBP-1 SDS correlated significantly with insulin levels, systolic blood pressure SDS, and various lipid parameters. Baseline IGFBP-1 SDS was lowest in SGA children with -575 GG genotype and significantly higher in SGA children with one or two copies of the A allele. In response to a given insulin level, children with the AA genotype had a significantly higher IGFBP-1 SDS compared to children with the GG genotype. CONCLUSION: Normal IGFBP-1 levels in lean, short, SGA children may reflect a normal metabolic state, despite reported hyperinsulinemia. IGFBP-1 is modulated by polymorphic variability and seems to be an additional player in the complex interaction between the IGF-IGFBP axis, glucose homeostasis, and lipid metabolism.
Asunto(s)
Proteína 1 de Unión a Factor de Crecimiento Similar a la Insulina/genética , Síndrome Metabólico/genética , Polimorfismo Genético , Regiones Promotoras Genéticas , Adolescente , Adulto , Peso al Nacer , Estatura/genética , Niño , Cartilla de ADN , Femenino , Prueba de Tolerancia a la Glucosa , Humanos , Recién Nacido , Recién Nacido Pequeño para la Edad Gestacional , Proteína 1 de Unión a Factor de Crecimiento Similar a la Insulina/sangre , Factor I del Crecimiento Similar a la Insulina/genética , Masculino , Síndrome Metabólico/sangre , Pubertad , Valores de Referencia , Triglicéridos/sangre , Adulto JovenRESUMEN
CONTEXT: The insulin-like growth factor (IGF)-system has been implicated in colorectal tumor carcinogenesis. Although both tumor expression levels and serum concentrations of IGF-system components are related to colorectal cancer risk, it is unknown whether IGF levels in tissue and serum are correlated. OBJECTIVE: The objective of this study was to determine expression levels of various IGF-system components in different locations of the colorectum, and to investigate whether normal tissue IGF expression levels are correlated with serum IGF-I and IGF-II concentrations. DESIGN: Biopsies from macroscopically normal mucosa at four locations in the colorectum (ascending, transverse, sigmoid colon, and rectum) and a fasting serum sample were obtained from 48 asymptomatic patients at increased risk of colorectal cancer. Expression levels of IGF-I, IGF-II, IGF-IR, IGF-IIR, and IGFBP-3 messenger RNA (mRNA) in tissue were quantitatively evaluated using real-time RT-PCR. Expression of IGF-IR protein in the ascending colon and rectum tissue specimens was assessed semi-quantitatively by immunohistochemistry. Serum IGF-I and IGF-II concentrations were determined using immunometric assays. RESULTS: With the exception of IGF-IIR, mRNA levels of all the IGF-system components investigated, as well as IGF-IR protein expression, were significantly higher in the rectum compared with the ascending colon (pAsunto(s)
Colon/metabolismo
, Proteína 3 de Unión a Factor de Crecimiento Similar a la Insulina/biosíntesis
, Factor II del Crecimiento Similar a la Insulina/biosíntesis
, Factor I del Crecimiento Similar a la Insulina/biosíntesis
, Receptor IGF Tipo 1/biosíntesis
, Receptor IGF Tipo 2/biosíntesis
, Recto/metabolismo
, Adulto
, Anciano
, Femenino
, Humanos
, Mucosa Intestinal/metabolismo
, Masculino
, Persona de Mediana Edad
, Datos de Secuencia Molecular
, ARN Mensajero/biosíntesis
, Suero
RESUMEN
BACKGROUND: Increased insulin-like growth factor (IGF)-I and IGF-II concentrations are related to increased colorectal cancer risk. Isoflavones have been associated with reduced colorectal cancer risk, and may affect the IGF system because of their weak estrogenic activity. The aim of the study was to investigate the effect of isolated isoflavones on serum concentrations of IGF system components. MATERIALS AND METHODS: We conducted a randomized, placebo-controlled, double-blinded, crossover trial in four hospitals in the Netherlands to investigate the effect of an 8-week supplementation with red clover-derived isoflavones (84 mg/d) on serum IGF-I concentrations. In addition, serum concentrations of IGF-II and IGF binding proteins (IGFBP)-1, IGFBP-2, and IGFBP-3 were assessed. Normal colorectal tissue biopsies were obtained after the first intervention period and mRNA expression of IGF-I, IGF-II, IGFBP-3, and IGF-IR was evaluated. Our study population consisted of 34 postmenopausal women with a family history of colorectal cancer or a personal history of colorectal adenomas. RESULTS: Isoflavone supplementation did not significantly affect serum concentrations of total IGF-I (mean relative within-person difference; IGF-I, -2.0%; 95% confidence interval, -8.0% to 3.9%). IGF-II and IGFBPs were also not significantly altered after isoflavone supplementation. Colorectal tissue mRNA expression of IGF system components did not significantly differ between individuals on isoflavone supplementation and those who received placebo. CONCLUSIONS: The results of our trial, supported by a qualitative review of soy trials published to date, suggest that isoflavones do not significantly affect circulating levels of IGF system components. Increased levels of IGF-I, as observed in most of these trials, are likely due to simultaneous protein supplementation.
Asunto(s)
Neoplasias Colorrectales/sangre , Factor II del Crecimiento Similar a la Insulina/metabolismo , Factor I del Crecimiento Similar a la Insulina/metabolismo , Isoflavonas/farmacología , Trifolium , Anciano , Estudios Cruzados , Método Doble Ciego , Femenino , Humanos , Proteínas de Unión a Factor de Crecimiento Similar a la Insulina/metabolismo , Persona de Mediana Edad , PlacebosRESUMEN
The insulin-like growth factor (IGF) system plays an important role in neuronal development and may contribute to the development of brain tumors. In this study, we studied mRNA expression levels of IGFs, insulin-like growth factor binding proteins (IGFBPs) and insulin-like growth factor receptors (IGFRs) in 27 pediatric medulloblastomas, 13 pediatric ependymomas and 5 control cerebella. Compared to normal cerebellum, mRNA levels of IGFBP-2 and IGFBP-3 were significantly increased in medulloblastomas and ependymomas. IGFBP-2 expression was indicative of poor prognosis in medulloblastomas, whereas IGFBP-3 mRNA levels were especially high in anaplastic ependymomas. IGFBP-5 and IGF-II mRNA levels were significantly increased in ependymomas compared to control cerebellum. Protein expression levels of IGFs and IGFBPs were analyzed in the cerebrospinal fluid (CSF) of 16 medulloblastoma, 4 ependymoma and 23 control patients by radioimmuno assay to determine whether they could be used as markers for residual disease after surgery. No aberrant CSF protein expression levels were found for ependymoma patients. In medulloblastoma patients, the IGFBP-3 protein levels were significantly higher than in ependymoma patients and controls. Moreover, enhanced levels of proteolytic fragments of IGFBP-3 were found in the CSF of medulloblastoma patients, being in concordance with a significantly increased IGFBP-3 proteolytic activity in the CSF of these patients. In conclusion, our data suggest that the IGF system is of importance in pediatric medulloblastomas and ependymomas. Larger studies should be conducted to validate the predictive values of the levels of intact IGFBP-3 and proteolytic fragments in CSF in the follow-up of medulloblastomas.
Asunto(s)
Neoplasias Encefálicas/metabolismo , Ependimoma/metabolismo , Proteínas de Unión a Factor de Crecimiento Similar a la Insulina/metabolismo , Factor II del Crecimiento Similar a la Insulina/metabolismo , Factor I del Crecimiento Similar a la Insulina/metabolismo , Meduloblastoma/metabolismo , Western Blotting , Neoplasias Encefálicas/sangre , Neoplasias Encefálicas/líquido cefalorraquídeo , Neoplasias Encefálicas/química , Estudios de Casos y Controles , Niño , Preescolar , Ependimoma/sangre , Ependimoma/líquido cefalorraquídeo , Ependimoma/química , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Proteína 1 de Unión a Factor de Crecimiento Similar a la Insulina/metabolismo , Proteína 2 de Unión a Factor de Crecimiento Similar a la Insulina/metabolismo , Proteína 3 de Unión a Factor de Crecimiento Similar a la Insulina/metabolismo , Proteína 4 de Unión a Factor de Crecimiento Similar a la Insulina/metabolismo , Proteína 5 de Unión a Factor de Crecimiento Similar a la Insulina/metabolismo , Proteína 6 de Unión a Factor de Crecimiento Similar a la Insulina/metabolismo , Proteínas de Unión a Factor de Crecimiento Similar a la Insulina/genética , Factor I del Crecimiento Similar a la Insulina/genética , Factor II del Crecimiento Similar a la Insulina/genética , Masculino , Meduloblastoma/sangre , Meduloblastoma/líquido cefalorraquídeo , Meduloblastoma/química , Análisis por Micromatrices , Valor Predictivo de las Pruebas , Pronóstico , ARN Mensajero/metabolismo , Radioinmunoensayo , Análisis de Supervivencia , Regulación hacia ArribaRESUMEN
Insulin-like growth factor-I (IGF-I) is an important growth factor associated with increased risk of premenopausal breast cancer. We conducted a randomized, placebo-controlled, double-blind, crossover trial to evaluate whether tomato-derived lycopene supplementation (30 mg/day for 2 mo) decreases serum levels of total IGF-I in premenopausal women with 1) a history of breast cancer (n=24) or 2) a high familial breast cancer risk (n=36). Also, IGF binding protein (IGFBP) increasing effects were evaluated. Lycopene supplementation did not significantly alter serum total IGF-I and other IGF system components in the 2 study populations combined. However, statistically significant discordant results were observed between the 2 study populations (i.e., P<0.05 for total IGF-I, free IGF-I, and IGFBP-3). Total IGF-I and IGFBP-3 were increased in the breast cancer survivor population [total IGF-I=7.0%, 95% confidence interval (CI)= -0.2 to 14.3%; IGFBP-3=3.3%, 95% CI=0.7-6.0%), and free IGF-I was decreased in the family history population (-7.6%, 95% CI= -14.6 to -0.6%). This randomized controlled trial shows that 2 mo of lycopene supplementation has no effect on serum total IGF-I in the overall study population. However, lycopene effects were discordant between the 2 study populations showing beneficial effects in high-risk healthy women but not in breast cancer survivors.