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The aging process induces neurochemical alterations in different brain regions, including hypothalamus. This pivotal area of the central nervous system (CNS) is crucial for detection and integration of nutritional and hormonal signals from the periphery of the body to maintain metabolic homeostasis. Astrocytes support the CNS homeostasis, energy metabolism, and inflammatory response, as well as increasing evidence has highlighted a critical role of astrocytes in orchestrating hypothalamic functions and in gliocrine system. In this study, we aimed to investigate the age-dependent mRNA expression of adenosine receptors, the insulin-like growth factor 1 receptor (IGF1R), and the hypoxia-inducible factor 1α (HIF1α), in addition to the levels of IGF1 and HIF1α in hypothalamic astrocyte cultures derived from newborn, adult, and aged rats. Our results revealed age-dependent changes in adenosine receptors, as well as a decrease in IGF1R/IGF1 and HIF1α. Of note, adenosine receptors, IGF1, and HIF1α are affected by inflammatory, redox, and metabolic processes, which can remodel hypothalamic properties, as observed in aging brain, reinforcing the role of hypothalamic astrocytes as targets for understanding the onset and/or progression of age-related diseases.

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OBJECTIVE: To analyze the relation between alterations in the growth hormone (GH)/insulin-like growth factor 1 (IGF-1) axis during the first 6 months of life and weight in children born in the lower-middle São Francisco region. METHODS: This is an analytical cohort and exploratory. Thirty children, were formed two groups, one of low birth weight children (LBW, n = 15) and another of normal weight (NBW = 15) were initially identified in a hospital and reapproached at 3 and 6 months of age. Birth weight and alterations in GH/IGF-1 curves were measured at birth and the third and sixth months of life. RESULTS: Weight gain during the 6 months of follow-up in newborns with a low birth weight was greater compared to newborns with a normal birth weight. All children who were born with a low birth weight had an altered GH/IGF-1 curve at birth (p = 0.002). Most newborns with a low birth weight maintained the alteration in the GH/IGF-1 curve at the third month of life (p = 0.027). Regarding the GH/IGF-1 curve at the sixth month, alteration persisted in greater proportion among children with a low birth weight. CONCLUSIONS: Alterations in insulin resistance markers, demonstrated by increased GH without a proportional increase in IGF-1, were observed to be significant in children with a low birth weight with greater adiposity in this group which may increase the risk of metabolic diseases in later life.

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Growth hormone (GH) is a classic pituitary-derived hormone crucial to body growth and metabolism. In the pituitary gland, GH production is stimulated by GH-releasing hormone and inhibited by somatostatin. GH secretion can also be induced by other peptides, such as ghrelin, which interacts with receptors present in somatotropic cells. It is well established that GH acts directly on target cells or indirectly by stimulating the production of insulin-like growth factors (IGFs), particularly IGF-1. Notably, such somatotropic circuitry is also involved in the development and function of immune cells and organs, including the thymus. Interestingly, GH, IGF-1, ghrelin, and somatostatin are expressed in the thymus in the lymphoid and microenvironmental compartments, where they stimulate the secretion of soluble factors and extracellular matrix molecules involved in the general process of intrathymic T-cell development. Clinical trials in which GH was used to treat immunocompromised patients successfully recovered thymic function. Additionally, there is evidence that the reduction in the function of the somatotropic axis is associated with age-related thymus atrophy. Treatment with GH, IGF-1 or ghrelin can restore thymopoiesis of old animals, thus in keeping with a clinical study showing that treatment with GH, associated with metformin and dehydroepiandrosterone, could induce thymus regeneration in healthy aged individuals. In conclusion, the molecules of the somatotrophic axis can be envisioned as potential therapeutic targets for thymus regeneration in age-related or pathological thymus involution.

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A physiological increase in cardiac workload results in adaptive cardiac remodeling, characterized by increased oxidative metabolism and improvements in cardiac performance. Insulin-like growth factor-1 (IGF-1) has been identified as a critical regulator of physiological cardiac growth, but its precise role in cardiometabolic adaptations to physiological stress remains unresolved. Mitochondrial calcium (Ca2+) handling has been proposed to be required for sustaining key mitochondrial dehydrogenase activity and energy production during increased workload conditions, thus ensuring the adaptive cardiac response. We hypothesized that IGF-1 enhances mitochondrial energy production through a Ca2+-dependent mechanism to ensure adaptive cardiomyocyte growth. We found that stimulation with IGF-1 resulted in increased mitochondrial Ca2+ uptake in neonatal rat ventricular myocytes and human embryonic stem cell-derived cardiomyocytes, estimated by fluorescence microscopy and indirectly by a reduction in the pyruvate dehydrogenase phosphorylation. We showed that IGF-1 modulated the expression of mitochondrial Ca2+ uniporter (MCU) complex subunits and increased the mitochondrial membrane potential; consistent with higher MCU-mediated Ca2+ transport. Finally, we showed that IGF-1 improved mitochondrial respiration through a mechanism dependent on MCU-mediated Ca2+ transport. In conclusion, IGF-1-induced mitochondrial Ca2+ uptake is required to boost oxidative metabolism during cardiomyocyte adaptive growth.

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Insulin-like growth factor-1 (IGF-1) plays critical roles in the development of the central nervous system (CNS), including the retina, regulating cell proliferation, differentiation, and survival. Here, we investigated the role of IGF-1 on retinal cell proliferation using primary cultures from rat neural retina. Our data show that IGF-1 stimulates retinal cell proliferation and regulates the expression of neurotrophic factors, such as interleukin-4 and brain-derived neurotrophic factor. In addition, our results indicates that IGF-1-induced retinal cell proliferation requires activation of multiple signaling pathways, including phosphatidylinositol 3-kinase, protein kinase Src, phospholipase-C, protein kinase C delta, and mitogen-activated protein kinase pathways. We further show that activation of matrix metalloproteinases and epidermal growth factor receptor is also necessary for IGF-1 enhancing retinal cell proliferation. Overall, these results unveil potential mechanisms by which IGF-1 ensures retinal cell proliferation and support the notion that manipulation of IGF-1 signaling may be beneficial in CNS disorders associated with abnormal cell proliferation.

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Gestational diabetes mellitus (GDM), is one of the most important pregnancy complications affecting approximately 15% of pregnant women. It is related to several gestational adverse outcomes in the fetus, e.g., macrosomia, shoulder dystocia, stillbirth, neonatal hypoglycemia, and respiratory distress. Women with GDM have a high risk of developing type 2 diabetes in the future. The pathogenesis of GDM is not completely understood; nevertheless, two factors could contribute to its development: ß-cell dysfunction and failure in insulin secretion in response to insulin resistance induced by gestation. Both processes, together with the physiological activities of the insulin-like growth factors (IGFs), play a crucial role in glucose transport to the fetus and hence, fetal growth and development. IGFs (both IGF-1 and IGF-2) and their binding proteins (IGFBPs) regulate glucose metabolism and insulin sensitivity. Maternal nutritional status determines the health of the newborn, as it has substantial effects on fetal growth and development. Maternal obesity and an energy-dense diet can cause an increase in insulin and IGF-1 serum levels, producing metabolic disorders, such as insulin resistance, GDM, and high birth weight (> 4,000 g) due to a higher level of body fat. In this way, in GDM pregnancies there is an increase in IGF-1 and IGF-2 serum levels, and a decrease in IGFBP-1 and 4 serum levels, suggesting the crucial role of the insulin/IGF system in this gestational outcome. Here, the present review tries to elucidate the role that energy-dense diets and the insulin/IGF-1 signaling pathway perform in GDM pregnancies.

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Myeloproliferative neoplasms (MPN) belong to a group of clonal diseases of hematopoietic stem cells characterized by aberrant proliferation of mature myeloid lineages. The constitutive activation of the JAK2/STAT signaling pathway is now well established to play a central role in MPN pathogenesis; however, accumulating evidence now indicates that the IGF1R-mediated signaling pathway contributes to the maintenance of the malignant phenotype. Studies using inhibitors of IGF1-mediated signaling have reported cytotoxic effects in cellular and murine models of MPN, but no consensus has been reached regarding the potency and efficacy of inhibitors of the IGF1R-related pathway in this context. In the present study, we compared the potency and efficacy of three inhibitors of IGF1R-related pathways in a JAK2V617F-driven cellular model. These inhibitors (NT157, OSI-906, and NVP-AEW54) present antineoplastic activity with similar efficacy in Ba/F3 JAK2V617F cells, with NT157 showing the greatest potency. Both the induction of apoptosis and reduction in cell proliferation were associated with the observed reduction in cell viability. Downregulation of JAK2/STAT signaling was an advantageous off-target effect of all three inhibitors. These preclinical studies reinforce the potential of the IGF1R-related pathway as a therapeutic target in MPN.

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OBJECTIVES: The aim of this study was to evaluate the safety and efficacy of cabergoline to control hypersomatotropism (HST) and diabetes mellitus (DM) in cats. METHODS: This was a prospective cohort study. Twenty-three cats with HST and concurrent DM were enrolled. Cats received a dose of 10 µg/kg cabergoline q48h PO for 6 months. Serum insulin-like growth factor 1 (IGF-1) and fructosamine concentrations, insulin dose and Insulin Resistance Index (IRI) were measured at the time of diagnosis of HST and at the start of cabergoline treatment (t0), and 3 months (t1) and 6 months (t2) during cabergoline treatment. RESULTS: A decrease and normalization of serum IGF-1 concentration was observed in 35% and 26% of cats, respectively. Median IGF-1 (t0: 1350 ng/ml [range 832-1501]; t1: 1284 ng/ml [range 365-1501]; t2: 1240 ng/ml [range 263-1501]; P = 0.016) decreased significantly. Twelve cats underwent diagnostic imaging of the pituitary area. The median pituitary height at t0 of cats that experienced an IGF-1 reduction (n = 5/12) was significantly lower compared with those that did not experience an IGF-1 reduction (n = 7/12) (3.2 mm [range 3.1-3.7] vs 6 mm [range 3.5-9.5]; P = 0.011). Median fructosamine (t0: 628 µmol/l [range 400-963]; t1: 404 µmol/l [range 249-780]; t2: 400 µmol/l [range 260-815]; P <0.0001), insulin dose (t0: 1.3 IU/kg [range 0.5-4.6]; t0: 0.5 IU/kg [range 0-2.3]; t2: 0.4 IU/kg [range 0-2.1]; P <0.0001) and IRI (t0: 800 µmolIU/kgl [range 257-2700]; t1: 300 µmolIU/kgl [range 0-1498]; t2: 250 µmolIU/kgl [range 0-1498]; P <0.0001) decreased significantly during cabergoline treatment. Eight cats achieved diabetic remission between months 1 and 6 of cabergoline treatment (median time to achieve remission: 3 months [range 1-6]). Three cats experienced asymptomatic hypoglycemia. CONCLUSIONS AND RELEVANCE: Cabergoline was effective in normalizing IGF-1 concentration in 26% of cats. Cabergoline improved diabetes control and was associated with remission of DM in 35% of cases. Cabergoline could be a treatment option for cats with HST and DM, especially in those cases with a relatively small pituitary tumor.

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Evidence points to an important role of the growth hormone (GH) in the aging process and longevity. GH-deficient mice are smaller, live longer than normal littermates, and females have an increased ovarian reserve. The aim of the study was to evaluate the role of GH in the ovarian reserve by evaluating DNA damage, macrophage infiltration, and granulosa cell number in primordial and primary follicles. Experiment 1 used GH-deficient Ames dwarf mice (df/df, n = 12) and their normal littermates (N/df, n = 12), receiving GH or saline injections. Experiment 2 included transgenic mice overexpressing bovine GH (bGH) (n = 6) and normal mice (N, n = 6). DNA damage (anti-γH2AX) and macrophage counting (anti-CD68) were evaluated by immunofluorescence. Female df/df mice had lower γH2AX foci intensity in both oocytes and granulosa cells of primordial and primary follicles (p < 0.05), indicating fewer DNA double-strand breaks (DSBs). GH treatment increased DSBs in both df/df and N/df mice. Inversely, bGH mice had a higher quantity of DSBs in both oocytes and granulosa cells of primordial and primary follicles (p < 0.05). Df/df mice showed ovarian tissue with less macrophage infiltration than N/df mice (p < 0.05) and GH treatment increased macrophage infiltration (p < 0.05). In contrast, bGH mice had ovarian tissue with more macrophage infiltration compared to normal mice (p < 0.05). The current study shows that GH increases DNA DSBs in oocytes and granulosa cells and raises macrophage infiltration in the ovaries, pointing to the role of the GH/IGF-I axis in maintenance of oocyte DNA integrity and ovarian macrophage infiltration in mice.

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Introdução: a hiperplasia adenotonsilar (HAT) é uma das causas mais comuns da Síndrome do Respirador Oral (SRO) devido à obstrução de via aérea superior em crianças e adolescentes. Tal afecção pode causar alterações ortodônticas, miofuncionais orofaciais, posturais, cardiopulmonares, antropométricas e polissonográficas. O diagnóstico precoce e indicação de Adenotonsilectomia (A&T) é essencial para reversão dessas consequências deletérias da SRO e restauração do bem estar biopsicossocial da criança.Objetivo: avaliar o estado nutricional, patência nasal, distúrbios do sono e fator de crescimento semelhante à insulina tipo 1 (IGF-1) em crianças de dois a doze anos de idade com SRO devido HAT grave e comparar com a reavaliação após seis meses de pós-cirúrgico das crianças operadas e com as demais que permanecem com obstrução da via aérea e aguardam a cirurgia na fila de espera do Sistema Único de Saúde. Métodos: trinta pacientes com SRO por HAT grave e indicação de A&T foram submetidos à avaliação antropométrica, polissonográfica, dosagem do IGF-1, rinomanométrica, teste alérgico cutâneo, questionário de padrão alimentar e prática de atividade física antes da A&T. Dez pacientes repetiram essa avaliação seis meses após o procedimento cirúrgico (grupo intervenção). Vinte pacientes aguardam a cirurgia na fila de espera do SUS e tiveram seus dados antropométricos e de IGF-1 reavaliados após seis meses com obstrução da via aérea (grupo controle). Resultados: trinta crianças realizaram a fase pré-operatória do estudo. A idade média foi de 5,6 anos (±2,17). Dezessete (56,7%) eram do sexo masculino e treze (43,3%) do sexo feminino. O teste cutâneo foi positivo em dezesseis indivíduos (53,3%) As médias dos escores Z de estatura por idade foi de -0,95 (±1,09); peso por idade de 0,17 (±1,42); índice de massa corporal (IMC) por idade de 0,31 (±1,36). A média do fluxo nasal inspiratório total (FNIT) foi de 444,63 ml/s (±161,02) e da patência nasal de 72,9% (±24,76). A média do índice de Apneia e Hipopneia (IAH) do sono foi de 4,95 ev/h (±4,07); da saturação mínima de oxihemoglobina no sono (Nadir de O2) de 78,93% (±6,00); da percentagem de sono com saturação menor que 90% (T90) de 4,16% (±5,48); da porcentagem do sono com ondas lentas (sono N3) de 37,62% (±9,61). A média do escore Z de IGF-1 foi de 0,72 (±1,30). O grupo intervenção e grupo controle não apresentaram alterações dos dados antropométricos com significância estatística. Houve diminuição do IGF-1 após a cirurgia sendo a média do escore Z de IGF-1 pré-operatório de 1,33 (±1,74) e pós-cirúrgico de -0,07 (±0,85); p=0,03. No grupo controle a variação do IGF-1 não foi significativa. O grupo intervenção não apresentou alteração com significância estatística do FNIT e da patência nasal. Nas dez crianças operadas foi constatada uma melhora da média do IAH de 5,25 ev/h (±4,29) para 1,99 ev/h (±1,16) e do T90 de 6,27% (±7,46) para 0,64% (±0,55) com p<0,05. Já o sono N3 e o Nadir de O2 não apresentaram alterações significativas. Não houve mudança qualitativa no padrão alimentar e na prática de atividade física nos dois períodos avaliados na vigência da pandemia de COVID19. Conclusão: Após A&T houve diminuição do IGF-1; p=0,03, melhora do IAH; p=0,03 e do T90; p=0,04. A cirurgia não modificou o estado nutricional com significância estatística nas dez crianças após 6 meses de pós-operatório. No pós-cirúrgico, não houve diferença estatística do FNIT e da patência nasal, assim como nessa amostra também não ocorreram alterações significativas do sono N3 e do Nadir de O2. O padrão alimentar e a prática de atividade física foram semelhantes qualitativamente no pré e no pós-operatório. Vinte crianças no grupo controle não tiveram alterações significativas dos dados antropométricos e do IGF-1 com seis meses de espera pela cirurgia e permanência da obstrução da via aérea. Não houve diferença estatística dos dados antropométricos e do IGF-1 entre o grupo controle e o grupo intervenção.

Introduction: adenotonsillar hyperplasia (ATH) is one of the most common causes of Mouth Breathing Syndrome (MBS) due to upper airway obstruction in children and adolescents. This condition can cause orthodontic, orofacial myofunctional, postural, cardiopulmonary, anthropometric and polysomnographic changes. Early diagnosis and indication of Adenotonsillectomy (T&A) is essential to revert these deleterious consequences of MBS and restore the child's biopsychosocial well-being. Objective: to evaluate the nutritional status, nasal patency, sleep disorders and insulin-like growth factor 1 (IGF-1) in children aged two to twelve years old with MBS due to severe ATH and compare with reassessment after six months post-surgical care of operated children and others who remain with airway obstruction and are waiting for surgery on the Unified Health System (UHS) waiting list. Methods: Thirty patients with MBS due to severe ATH and indication for T&A were submitted to anthropometric, polysomnographic, IGF-1 dosage, rhinomanometric, allergic skin test, dietary pattern questionnaire and physical activity practice before T&A. Ten patients repeated this evaluation six months after the surgical procedure (intervention group). Twenty patients were waiting for surgery on the UHS waiting list and had their anthropometric and IGF-1 data reassessed after six months with airway obstruction (control group). Results: Thirty children underwent the preoperative phase of the study. The mean age was 5.6 years (±2.17). Seventeen (56.7%) were male and thirteen (43.3%) were female. The skin test was positive in sixteen individuals (53.3%) The average Z-scores for height for age were -0.95 (±1.09); weight for age 0.17 (±1.42); body mass index (BMI) for age of 0.31 (±1.36). The mean total inspiratory nasal flow (TINF) was 444.63 ml/s (±161.02) and nasal patency was 72.9% (±24.76). The average sleep apnea and hypopnea index (AHI) was 4.95 ev/h (±4.07); minimum oxyhemoglobin saturation during sleep (O2 Nadir) of 78.93% (±6.00); percentage of sleep with saturation lower than 90% (T90) of 4.16% (±5.48); percentage of sleep with slow waves (N3) of 37.62% (±9.61). The mean IGF-1 Z-score was 0.72 (±1.30). The intervention group and control group did not show statistically significant changes in anthropometric data. There was a decrease in IGF-1 after surgery, with a mean preoperative IGF-1 Z-score of 1.33 (±1.74) and postoperative value of -0.07 (±0.85); p=0.03. In the control group, the IGF-1 variation was not significant. The intervention group did not show statistically significant changes in TINF and nasal patency. In the ten operated children, an improvement in the mean AHI from 5.25 ev/h (±4.29) to 1.99 ev/h (±1.16) and T90 of 6.27% (±7. 46) to 0.64% (±0.55) with p<0.05. On the other hand, N3 sleep and O2 Nadir showed no significant changes. There was no qualitative change in dietary patterns and physical activity in the two periods evaluated during the COVID19 pandemic. Conclusion: After T&A there was a decrease in IGF-1; p=0.03, AHI improvement; p=0.03 and T90 too; p=0.04. The surgery did not change the nutritional status with statistical significance in the ten children after 6 months postoperatively. Post-surgery, there was no statistical difference in TINF and nasal patency, as well as in this sample there were no significant changes in N3 sleep and O2 Nadir either. The dietary pattern and the practice of physical activity were qualitatively similar before and after the operation. Twenty children in the control group did not have significant alterations in anthropometric data and IGF-1 after six months of waiting for the surgery and the remaining airway obstruction. There was no statistical difference in anthropometric and IGF-1 data between the control and intervention groups.

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ABSTRACT Introduction Skeletal muscle injuries account for 10% to 50% of treadmill sports injuries. Insulin-like growth factor (IGF) is a family of polypeptides with both insulin-like anabolic and growth-promoting effects. Sports play a vital role in the recovery of skeletal muscle injuries. Objective The paper analyzes the ability of insulin-like growth factor 1 (IGF-1) to repair skeletal muscle injury caused by treadmill exercise. Method We injected drugs under the wound after exercise-induced injury in rats. The control group was injected with saline, and the experimental group was injected with an insulin-like growth factor. We conduct histological and electron microscopic structural analysis of rats, Results: After an injury, the experimental group formed a basal lamina protective film earlier than the control group, activated myoblasts, formed myofilaments, formed myotubes, and fused into muscle fibers earlier than the control group. The healing quality was also better. The experimental group was endogenous. The mRNA content of sex IGF-1 and IGF-2 both increased earlier than the control group. Conclusion Local injection of exogenous insulin-like growth factor-1 can stimulate the proliferation of myoblasts and accelerate the post-traumatic repair process of skeletal muscle caused by treadmill sports. Level of evidence II; Therapeutic studies - investigation of treatment results.

RESUMO Introdução As lesões do músculo esquelético representam de 10% a 50% das lesões em esteira esportiva. O fator de crescimento semelhante à insulina (IGF) é uma família de polipeptídeos com efeitos anabólicos e de promoção do crescimento semelhantes à insulina. Os esportes desempenham um papel vital na recuperação de lesões musculares esqueléticas. Objetivo o artigo analisa a capacidade do fator de crescimento semelhante à insulina 1 (IGF-1) em reparar lesões musculares esqueléticas causadas por exercícios em esteira. Método Injetamos drogas sob a ferida após lesão induzida por exercício em ratos. O grupo controle foi injetado com solução salina e o grupo experimental foi injetado com um fator de crescimento semelhante à insulina. Realizamos análises histológicas e microscópicas eletrônicas estruturais de ratos. Resultados Após a lesão, o grupo experimental formou um filme protetor da lâmina basal mais cedo do que o grupo controle, mioblastos ativados, miofilamentos formados, miotubos formados e fundidos em fibras musculares mais cedo do que o grupo controle. A qualidade da cura também foi melhor. O grupo experimental era endógeno. O conteúdo do sexo IGF-1 e IGF-2 mRNA aumentou mais cedo do que no grupo de controle. Conclusão A injeção local de fator de crescimento semelhante à insulina 1 exógeno pode estimular a proliferação de mioblastos e acelerar o processo de reparo muscular esquelético pós-traumático causado por esportes em esteira. Nível de evidência II; Estudos terapêuticos: investigação dos resultados do tratamento.

RESUMEN Introducción Las lesiones del músculo esquelético representan del 10% al 50% de las lesiones deportivas en cinta. El factor de crecimiento semejante a la insulina (IGF) es una familia de polipéptidos con efectos anabólicos y estimulantes del crecimiento semejantes a la insulina. Los deportes juegan un papel vital en la recuperación de las lesiones del músculo esquelético. Objetivo El artículo analiza la capacidad del factor de crecimiento semejante a la insulina 1 (IGF-1) para reparar la lesión del músculo esquelético causada por el ejercicio en cinta. Método inyectamos drogas debajo de la herida después de una lesión inducida por el ejercicio en ratas. Al grupo de control se le inyectó solución salina y al grupo experimental se le inyectó un factor de crecimiento semejante a la insulina. Realizamos análisis estructurales histológicos y microscópicos electrónicos de ratas, Resultados: Después de una lesión, el grupo experimental formó una película protectora de la lámina basal antes que el grupo de control, activó mioblastos, formó miofilamentos, formó miotubos y se fusionó en fibras musculares antes que el grupo de control. La calidad de curación también fue mejor. El grupo experimental fue endógeno. El contenido de ARNm de IGF-1 e IGF-2 de sexo aumentaron antes que en el grupo de control. Conclusión La inyección local de factor de crecimiento semejante a la insulina 1 exógeno puede estimular la proliferación de mioblastos y acelerar el proceso de reparación postraumático del músculo esquelético causado por los deportes en cinta. Nivel de evidencia II; Estudios terapéuticos: investigación de los resultados del tratamiento.

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SUMMARY: In testicular differentiation, somatic cells must adopt a specific destiny towards sustentacular, peritubular and interstitial cells, being fundamental for the morphogenesis of seminiferous tubules, mediated by morphogens such as Desert Hedgehog (DHH), insulin-like growth factor-1 (IGF-1) and fibroblastic growth factor 2 (FGF-2). Its alteration could be related to failures in the development mechanisms, such as those caused by valproic acid (VPA), which can be reversed with vitamin E (VE). The objective of the study was to evaluate the epithelial-mesenchymal transition (EMT) in the testicular development of mice exposed to VPA and VE. 12 groups of pregnant female mice were formed that were separated by days post-coital (dpc) at 12.5 dpc, 17.5 dpc and 6 weeks postnatal, each one subdivided into 4 groups of 5 pregnant women each. Subgroups received different treatments from the beginning to the end of gestation orally: 600 mg/kg of VPA, 600 mg/kg of VPA and 200 IU of VE, 200 IU of VE and the control group 0.3 mL of 0.9% physiological solution. Immunohistochemistry was performed for the detection of DHH, IGF-1 and FGF-2. Immunolocalization of DHH was observed in all stages, with more evident significant differences in integrated optical density (IOD) and percentage of immunoreaction area at 6 weeks postnatal, being lower in the VPA group. In IGF-1, lower intensity and distribution of immunostaining was observed in the fetal and pubertal stages in the VPA groups, a similar situation with FGF-2, but only evident at 17.5 dpc, with significant differences. These results demonstrate that VPA can alter EMT between somatic cells in testicular development, with VE being an agent capable of attenuating this process.

RESUMEN: En la diferenciación testicular, es necesario que las células somáticas adopten un destino específico hacia células sustentaculares, peritubulares e intersticiales, siendo fundamental para la morfogénesis de los túbulos seminíferos, mediado por morfógenos como Desert Hedgehog (DHH), Factor de Crecimiento Fibroblástico 2 (FGF-2) y Factor de Crecimiento símil a Insulina (IGF-1). Su alteración se podría relacionar a fallas en los mecanismos de desarrollo, como los que ocasiona el ácido valproico (VPA), los cuales pueden ser revertidos con la vitamina E (VE). El objetivo de estudio fue evaluar la transición epitelio-mesenquimática (EMT) en el desarrollo testicular de ratones expuestos a VPA y VE. Se conformaron 12 grupos de ratones hembra gestantes que se separaron por días post-coital (dpc) a los 12.5 dpc, 17.5 dpc y 6 semanas post-natal, cada uno subdividido en 4 grupos de 5 gestantes cada uno. Cada subgrupo recibió diferentes tratamientos desde el inicio hasta el término de la gestación vía oral: 600 mg/kg de VPA, 600 mg/kg de VPA y 200 UI de VE, 200 UI de VE y el grupo control 0,3 mL de solución fisiológica 0,9%. Se realizó técnica inmunohistoquímica para la detección de DHH, IGF-1 y FGF-2. Se observó la inmunolocalización de DHH en todos los estadios, con diferencias significativas más evidentes en la densidad óptica integrada (IOD) y porcentaje de área de inmunoreacción a las 6 semanas post-natal, siendo menor en el grupo VPA. En IGF-1, se observó en la etapa fetal y puberal menor intensidad y distribución de la marcación en los grupos VPA, situación similar con la inmunomarcación de FGF-2, pero sólo evidenciándose a los 17.5 dpc, con diferencias significativas. Estos resultados demuestran que el VPA puede alterar la EMT entre las células somáticas en el desarrollo testicular, siendo la VE un agente capaz de atenuar este proceso.

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Addition effects of insulin-like growth factor-1 (IGF-1) and its synthetic analogue insulin-like growth factor-1 recombinant-3 (LongR3-IGF-1) after in vitro maturation (IVM) of cattle cumulus-oocyte complexes (COCs) were compared and evaluated on meiotic progression, apoptosis and profile genes of oocyte competence (GDF9, BMP15, BAX, BCL2, OOSP1, IGFBP2, IGBFP4 and IGFBP5), and their respective cumulus cells (AREG, EGFR, FSHR, COX2, BAX, BCL2, IGFBP2, IGFBP4 and IGFBP5). The 739 COCs (n = 10 pools) of bovine ovaries were collected, selected and matured with IGF-1 (100 ng/mL), LongR3-IGF-1 (100 ng/mL), and in two control groups with 0.1% polyvinyl alcohol (PVA) or 10% fetal bovine serum (FBS), for 22-24 h. The statistical analysis was performed by a linear mixed effects model, ANOVA and Tukey tests. There was no statistical difference between experimental groups taken into account the meiotic progression and apoptosis (P > 0.05). Nevertheless, there were statistical differences (P ≤ 0.05) among FBS, IGF-1 and LongR3-IGF-1 groups for IGFBP4 gene expression, and among PVA, IGF-1 and LongR3-IGF-1 for COX2 gene expression in cumulus cells. Moreover, statistical difference was found for BCL2 gene expression between IGF-1, FBS and PVA groups and for IGFBP4 gene expression between LongR3-IGF-1, PVA and FBS in oocytes. There was no statistical difference between experimental groups for other genes evaluated. These results showed a good performance of IVM of bovine oocytes in the presence of LongR3-IGF-1 and the possibility of replacement of IGF-1 and FBS.

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The objective of this study was to evaluate the effects of in ovo injection with glycerol (GLY) and insulin-like growth factor (IGF-I) on hatchability, biochemical parameters, intestinal morphometry, performance, and carcass characteristics of broiler chickens. A total of 400 fertilised eggs were distributed into five experimental groups. The treatments were arranged as non-injected (control), saline solution injected (0.9% NaCl solution), GLY solution injected (10 nmol/ml), IGF-I solution injected (100 ng/ml), and GLY + IGF-I solution injected. At 17.5 d of incubation, 0.5 ml of each solution was injected into the amniotic fluid of each egg of the injected groups. The injection of different solutions did not influence the hatchability and incubation time of the eggs. Compared to intact eggs, IGF-I and IGF-I+ GLY increased (p < 0.01) the blood IGF-I at hatching. Higher hepatic glycogen was observed (p < 0.05) with GLY or IGF-I. The tested substances decreased (p = 0.02) the fructose 1,6-biphosfate phosphatase activity but did not affect glycaemia. No difference in performance was observed in the first week. Higher feed intake and weight gain with lower feed conversion ratio was obtained ( p  < 0.05) with IGF-I at 14 d. At 21 d, higher weight gain was obtained (p = 0.05) with IGF-I, GLY, IGF-I, and GLY + IGF-I, resulting (p < 0.01) in birds with greater weight gain at 35 and 42 d of age. GLY provided higher villus height in the ileum at hatching and at 7 d of age. The tested solutions increased the relative weight of the liver at hatching. At 42 d of age, no carcass characteristics were influenced. It is concluded that GLY and IGF-I, together or separately, can be used in the in ovo feeding to improve the post-hatch performance of broilers, without affecting hatchability and carcass composition.

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Insulin-like growth factor-1 (IGF-1) is regarded as a crucial clinically significant therapeutic agent against several pathological conditions. Recently, recombinant DNA (rDNA) technology has enabled the production of many drugs of rDNA-origin including IGF-1. Securing a readily available supply of IGF-1 is invaluable to clinical research and biotechnological domains. In this work, the cloning of a full-length bovine IGF-1 cDNA and the successful expression of its cognate recombinant IGF-1 protein is reported. Single-strand cDNA was prepared from liver tissues, through the specific reverse transcription (RT) of IGF-1 mRNA. Subsequently, a PCR amplicon of ~543bp was successfully amplified. Recombinant pTARGET™ vector harboring IGF-1 insert was successfully cloned into competent E. coli JM109 cells. SDS-PAGE analysis revealed that the recombinant IGF-1 has been expressed at the expected size of 7.6kDa. The outcome provides a robust basis for transecting the recombinant pTARGETTM vector, harboring the IGF-1 cDNA insert, into mammalian cells. Optimal initial glucose concentration was found to be 10g/l with corresponding protein concentration of 6.2g/l. The proliferative biological activity crude recombinant IGF-1 protein was verified on HeLa cell lines. This is envisaged to facilitate large-scale production of recombinant IGF-1 protein, thereby enabling thorough investigation of its clinical and pharmaceutical effects.(AU)

O fator de crescimento semelhante à insulina-1 (IGF-1) é considerado um agente terapêutico clinicamente significativo contra várias condições patológicas. Recentemente, a tecnologia de DNA recombinante (rDNA) permitiu a produção de muitos medicamentos de origem rDNA, incluindo o IGF-1. Garantir um suprimento prontamente disponível de IGF-1 é inestimável para pesquisas clínicas e domínios biotecnológicos. Neste trabalho, relata-se a clonagem de um cDNA de IGF-1 bovino de comprimento total e a expressão bem-sucedida de sua proteína IGF-1 recombinante cognata. O cDNA de cadeia simples foi preparado a partir de tecidos do fígado, por meio da transcrição reversa específica (RT) do mRNA de IGF-1. Posteriormente, um amplificador de PCR de ~ 543pb foi amplificado com sucesso. O vetor pTARGET™ recombinante contendo a inserção de IGF-1 foi clonado com sucesso em células competentes E. coli JM109. A análise por SDS-PAGE revelou que o IGF-1 recombinante foi expresso no tamanho esperado de 7,6kDa. O resultado fornece uma base robusta para a transferência do vetor pTARGETTMTM recombinante, abrigando a inserção de cDNA de IGF-1 em células de mamíferos. Verificou-se que a concentração inicial ideal de glicose é 10g/L, com a concentração de proteína correspondente de 6,2g/L. A proteína IGF-1 recombinante bruta de atividade biológica proliferativa foi verificada nas linhas celulares HeLa. É previsto que isso facilite a produção da proteína IGF-1 recombinante em larga escala, permitindo, assim, uma investigação completa dos seus efeitos clínicos e farmacêuticos.(AU)

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RESUMO

Insulin-like growth factor-1 (IGF-1) is regarded as a crucial clinically significant therapeutic agent against several pathological conditions. Recently, recombinant DNA (rDNA) technology has enabled the production of many drugs of rDNA-origin including IGF-1. Securing a readily available supply of IGF-1 is invaluable to clinical research and biotechnological domains. In this work, the cloning of a full-length bovine IGF-1 cDNA and the successful expression of its cognate recombinant IGF-1 protein is reported. Single-strand cDNA was prepared from liver tissues, through the specific reverse transcription (RT) of IGF-1 mRNA. Subsequently, a PCR amplicon of ~543bp was successfully amplified. Recombinant pTARGET™ vector harboring IGF-1 insert was successfully cloned into competent E. coli JM109 cells. SDS-PAGE analysis revealed that the recombinant IGF-1 has been expressed at the expected size of 7.6kDa. The outcome provides a robust basis for transecting the recombinant pTARGETTM vector, harboring the IGF-1 cDNA insert, into mammalian cells. Optimal initial glucose concentration was found to be 10g/l with corresponding protein concentration of 6.2g/l. The proliferative biological activity crude recombinant IGF-1 protein was verified on HeLa cell lines. This is envisaged to facilitate large-scale production of recombinant IGF-1 protein, thereby enabling thorough investigation of its clinical and pharmaceutical effects.(AU)

O fator de crescimento semelhante à insulina-1 (IGF-1) é considerado um agente terapêutico clinicamente significativo contra várias condições patológicas. Recentemente, a tecnologia de DNA recombinante (rDNA) permitiu a produção de muitos medicamentos de origem rDNA, incluindo o IGF-1. Garantir um suprimento prontamente disponível de IGF-1 é inestimável para pesquisas clínicas e domínios biotecnológicos. Neste trabalho, relata-se a clonagem de um cDNA de IGF-1 bovino de comprimento total e a expressão bem-sucedida de sua proteína IGF-1 recombinante cognata. O cDNA de cadeia simples foi preparado a partir de tecidos do fígado, por meio da transcrição reversa específica (RT) do mRNA de IGF-1. Posteriormente, um amplificador de PCR de ~ 543pb foi amplificado com sucesso. O vetor pTARGET™ recombinante contendo a inserção de IGF-1 foi clonado com sucesso em células competentes E. coli JM109. A análise por SDS-PAGE revelou que o IGF-1 recombinante foi expresso no tamanho esperado de 7,6kDa. O resultado fornece uma base robusta para a transferência do vetor pTARGETTMTM recombinante, abrigando a inserção de cDNA de IGF-1 em células de mamíferos. Verificou-se que a concentração inicial ideal de glicose é 10g/L, com a concentração de proteína correspondente de 6,2g/L. A proteína IGF-1 recombinante bruta de atividade biológica proliferativa foi verificada nas linhas celulares HeLa. É previsto que isso facilite a produção da proteína IGF-1 recombinante em larga escala, permitindo, assim, uma investigação completa dos seus efeitos clínicos e farmacêuticos.(AU)

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The aim of this study was to evaluate the effect of growth hormone (GH) deficiency in primordial follicle reserve, DNA damage and macrophage infiltration in the ovaries of young mice. Ovaries from six-month-old GH-deficient Ames Dwarf (df/df) and Normal (N/df) mice were used. The number of primordial follicles was higher in df/df mice (p = 0.0026). Also, df/df mice had a lower number of primary (p = 0.023), secondary (p = 0.0052) and tertiary (p = 0.019) follicles. These findings indicate a slower rate of primordial follicle activation in df/df mice. Female df/df mice had decreased γH2AX foci intensity in oocytes of primordial (p = 0.015) and primary (p = 0.0004) follicles compared to N/df mice. Also, df/df mice had reduced γH2AX intensity in granulosa cells of primordial (p = 0.0002) and primary (p < 0.0001) follicles. Overall, this indicate to us that df/df mice accumulate less DNA damage in the ovarian reserve compared to N/df mice. Additionally, macrophage infiltration was also reduced in ovaries of df/df mice compared to N/df mice (p = 0.033). Interestingly, df/df mice had a reduced number of granulosa cells around primordial (p = 0.0024) and primary (p = 0.007) follicles compared to N/df mice. Also, df/df mice had a small diameter of primordial follicle nuclei (p = 0.0093), secondary follicle oocyte (p = 0.046) and tertiary follicle (p = 0.012). This points to the role of granulosa cell proliferation and oocyte growth for primordial follicle activation. The current study points to the role of the GH/IGF-I axis in extending lifespan of reproductive health, along with maintenance of oocyte DNA integrity and reduced ovarian inflammation.

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Testosterone has been demonstrated to antagonize doxorubicin-induced cardiomyocyte senescence. However, whether testosterone prevents the paraquat-induced cardiomyocyte senescence is largely unknown. The detection of SA-β-gal activity was performed using senescence β-gal staining kit and the reactive oxygen species levels were determined by reactive oxygen species assay kit. The plasmids for insulin-like growth factor 1 shRNA (sh-mIGF-1), sirtuin-1 shRNA (sh-SIRT1), scramble shRNA (sh-NC), overexpressing mIGF-1 (mIGF-1), overexpressing SIRT1 (SIRT1), and negative controls (NC) were obtained for this study. The expression of target genes was detected using quantitative real-time PCR, immunolabeling, and western blot. We found that testosterone significantly delayed the paraquat-induced HL-1 cardiomyocyte senescence as evidenced by decreasing senescence-associated β-galactosidase activity and reactive oxygen species generation, which were accompanied by the up-regulated expression of mIGF-1 and SIRT1. RNA interference to reduce mIGF-1 and SIRT1 expression showed that testosterone prevented paraquat-induced HL-1 senescence via the mIGF-1/SIRT1 signaling pathway. Furthermore, myocardial contraction was evaluated by expression of genes of the contractile proteins/enzymes, such as α-myosin heavy chain 6 (MHC6), α-myosin heavy chain 7 (MHC7), α-skeletal actin (ACTA-1), and sarco/endoplasmic reticulum calcium ATPase-2 (SERCA2). Testosterone adjusted the above four gene expressions and the adjustment was blocked by mIGF-1 or SIRT1 inhibition. Our findings suggested that the mIGF-1/SIRT1 signaling pathway mediated the protective function of testosterone against the HL-1 cardiomyocyte senescence by paraquat, which provided new clues for the mechanisms underlying the anti-aging role of testosterone in cardiomyocytes.

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OBJECTIVE: To examine whether daily zinc and/or multivitamin supplementation reduce biomarkers of environmental enteric dysfunction (EED), systemic inflammation, or markers of growth in a sample of infants from Dar es Salaam, Tanzania. STUDY DESIGN: Subgroup analysis of infants participating in a randomized, double-blind, placebo-controlled trial received daily oral supplementation of zinc, multivitamins, zinc + multivitamins, or placebo for 18 months starting at 6 weeks of age. EED (anti-flagellin and anti-lipopolysaccharide immunoglobulins), systemic inflammation (C-reactive protein and alpha-1-acid glycoprotein), and growth biomarkers (insulin-like growth factor-1 and insulin-like growth factor binding protein-3) were measured via enzyme-linked immunosorbent assay in a subsample of 590 infants at 6 weeks and 6 months of age. EED biomarkers also were measured in 162 infants at 12 months of age. RESULTS: With the exception of anti-lipopolysaccharide IgG concentrations, which were significantly greater in infants who received multivitamins compared with those who did not (1.41 ± 0.61 vs 1.26 ± 0.65, P = .006), and insulin-like growth factor binding protein-3 concentrations, which were significantly lower in children who received zinc compared with those who did not (981.13 ± 297.59 vs 1019.10 ± 333.01, P = .03), at 6 months of age, we did not observe any significant treatment effects of zinc or multivitamins on EED, systemic inflammation, or growth biomarkers. CONCLUSIONS: Neither zinc nor multivitamin supplementation ameliorated markers of EED or systemic inflammation during infancy. Other interventions should be prioritized for future trials. TRIAL REGISTRATION: Clinicaltrials.gov: NCT00421668.

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Resumen: Se comunica el caso de una paciente de 46 años de edad con antecedente de artritis de articulaciones metacarpofalángicas, interfalángicas proximales, carpos y codos de seis meses de duración. Tres años antes sufría cefalea y se le detectó diabetes mellitus. El examen físico mostró artritis de articulaciones de manos, carpos y codos. En vista de cambios sugerentes de acromegalia en la cara y las extremidades se solicitaron más estudios. Debido a las concentraciones elevadas de hormona del crecimiento e IGF-1, la imagen de resonancia magnética del cráneo, existencia de poliartritis, actividad de enfermedad de 28 articulaciones (DAS28) de 7.3, factor reumatoide e hiperglucemia, se establecieron los diagnósticos de tumor de hipófisis con acromegalia, artritis reumatoide activa y diabetes mellitus. A la paciente se le practicó cirugía trans-esfenoidal del tumor de hipófisis, que resultó en normalización de las concentraciones de hormona del crecimiento, IGF-1, glucosa y cefalea. Su artritis entró en remisión con metotrexato oral.

Abstract: This paper reports the case of a 46-year-old woman with a 6-month history of duration of arthritis of metacarpophalangeal, proximal interphalangeal, carpal and elbow joints of 6 months duration. Three years before she reported headache and diabetes mellitus. Due to changes suggestive of acromegaly on the face and extremities more studies were requested. In view of the elevated levels of GH, IGF-1, positive rheumatoid factor, arthritis, hyperglycemia, and the presence of a pituitary adenoma, the patient was diagnosed with acromegaly, rheumatoid arthritis and diabetes mellitus. The patient underwent trans-sphenoidal resection, which resulted in normalization of hyperglycemia, headache, eradication of the tumor mass, GH and IGF-1 levels and remission of her rheumatoid arthritis with oral methotrexate.