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1.
J Anim Sci ; 99(3)2021 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-33587143

RESUMO

The aim of this study was to evaluate the effect of bovine somatotropin (bST) on fetal and placental development during the first third of gestation in beef heifers. Angus heifers (n = 97) were randomly assigned to either receive a 500-mg injection of bST (BST) biweekly on days 0, 15, 29, 43, and 57 of gestation or not receive bST (CTL) throughout the experiment. Body weight (BW) was assessed on days -9, -3, 0, 15, 22, 29, 43, 50, 57, 64, and 77, while blood samples were collected on days 0, 22, 50, and 64. Pregnancy status was determined via transrectal ultrasonography on days 29 and 64. A subset of pregnant heifers (BST, n = 7; CTL, n = 5) were harvested on day 84, and complete gravid reproductive tracts and liver tissue were collected for analysis. Cytochrome P450 1A (CYP1A), 2C (CYP2C), 3A (CYP3A), and uridine 5'-diphospho-glucuronosyltransferase (UGT) activities were determined. Mean change in BW and average daily gain of heifers between fixed-time artificial insemination (day 0) and day 77 did not differ between treatments (P ≥ 0.05). Mean concentrations of insulin-like growth factor 1 (IGF-1) were greater (P < 0.001) in BST (347 ± 27.7 ng/mL) compared with CTL (135 ± 32.8 ng/mL) heifers. Mean placental weight, fetal membrane weight, uterine weight, and ovarian and corpus luteum (CL) weights, as well as fetal morphometric data, did not differ (P ≥ 0.05) between treatments. However, BST heifers had greater (P = 0.03) quantities of combined fetal fluid compared with CTL (521.6 ± 22.9 vs. 429.6 ± 27.14 g, respectively). Tendencies were observed for BST heifers to have reproductive tracts with fewer placentomes (P = 0.08) and fetuses with greater umbilical diameters (P = 0.09) compared with CTL. The activity of CYP1A did not differ (P ≥ 0.05) within the maternal and fetal liver, caruncle, cotyledon, or CL tissue samples between treatments. Furthermore, CYP3A activity was only observed in maternal liver samples and was not different between treatments (P ≥ 0.05). Interestingly, CYP2C activity was greater (P = 0.01) in the liver of BST vs. CTL heifers, and UGT activity was greater (P = 0.02) in the CL from BST heifers compared with CTL. In conclusion, the administration of bST during the first third of gestation increased plasma concentrations of IGF-1, which resulted in an increase in fetal fluid, decrease in placentome number, and greater umbilical diameter, but failed to alter fetal development.


Assuntos
Hormônio do Crescimento , Inseminação Artificial , Animais , Bovinos , Eicosanoides , Feminino , Hormônio do Crescimento/farmacologia , Inseminação Artificial/veterinária , Fator de Crescimento Insulin-Like I , Gravidez , Esteroides
2.
Aging (Albany NY) ; 13(2): 1633-1648, 2020 12 28.
Artigo em Inglês | MEDLINE | ID: mdl-33378746

RESUMO

Histone modifications, specifically in the lysine residues of histone H3, have been implicated in lifespan regulation in several model organisms. Our previous studies showed that growth hormone (GH) treatment during early life can dramatically influence lifespan in long-lived Ames dwarf mice. However, the effects of this hormonal intervention on epigenetic modifications have never been examined. In this study, we sought to compare tissue-specific histone H3 lysine methylation and acetylation markers in Ames dwarf and wild type (WT) mice and to determine how these markers are affected by early-life GH intervention. Ames dwarf mice exhibited suppressed H3K4me in both hepatic and brain tissues, while showing elevated H3K27me in the brain. Early-life GH intervention significantly altered the histone H3 markers in those tissues. Furthermore, early GH intervention increased expression of histone H3 acetylation at multiple lysine residues in a tissue-specific manner. This included changes in H3K14ac and H3K18ac in the liver and brain, H3K18ac in visceral adipose tissue and H3K9ac, H3K14ac and H3K27ac in subcutaneous adipose tissue. This study serves as an initial, but important step in elucidating the epigenetic mechanisms by which hormonal signals during early life can influence aging and longevity in mammals.


Assuntos
Encéfalo/efeitos dos fármacos , Nanismo Hipofisário/metabolismo , Epigênese Genética/efeitos dos fármacos , Hormônio do Crescimento/farmacologia , Histonas/efeitos dos fármacos , Fígado/efeitos dos fármacos , Acetilação/efeitos dos fármacos , Animais , Encéfalo/metabolismo , DNA (Citosina-5-)-Metiltransferase 1/efeitos dos fármacos , DNA (Citosina-5-)-Metiltransferase 1/genética , DNA (Citosina-5-)-Metiltransferases/efeitos dos fármacos , DNA (Citosina-5-)-Metiltransferases/genética , Modelos Animais de Doenças , Nanismo Hipofisário/genética , Proteína Potenciadora do Homólogo 2 de Zeste , Hormônio do Crescimento/deficiência , Código das Histonas/efeitos dos fármacos , Histonas/metabolismo , Proteínas de Homeodomínio/genética , Terapia de Reposição Hormonal , Gordura Intra-Abdominal/efeitos dos fármacos , Gordura Intra-Abdominal/metabolismo , Fígado/metabolismo , Longevidade/genética , Metilação/efeitos dos fármacos , Camundongos , Gordura Subcutânea/efeitos dos fármacos , Gordura Subcutânea/metabolismo
3.
PLoS One ; 15(6): e0235270, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32589657

RESUMO

Growth hormone (GH) activates multiple signal transduction pathways. To investigate these pathways, we identified novel genes whose transcription was induced by GH in the liver of hypophysectomized (HPX) rats using the suppression subtractive hybridization technique. We found that regulator of calcineurin 1 (Rcan1) mRNA was upregulated by GH administration. RCAN1 regulates the activity of calcineurin, a Ca/calmodulin-dependent phosphatase. Rcan1 encodes two major transcripts, Rcan1-1 and Rcan1-4, resulting from differential promoter use and first exon choice. We found that a single injection of GH increased the levels of Rcan1-4 mRNA and RCAN1-4 protein transiently, but did not increase Rcan1-1 mRNA in HPX rat liver. Then the molecular mechanism of GH to induce Rcan1-4 transcription was examined in rat hepatoma H4IIE cells. Experiments using inhibitors suggested that c-JUN N-terminal kinase was required for the induction of Rcan1-4 mRNA by GH. GH increased the levels of phosphorylated c-JUN protein and c-Jun mRNA in HPX rat liver. The luciferase and electrophoretic mobility shift assays showed that c-JUN upregulated Rcan1-4 mRNA by binding to the cAMP-responsive element in the upstream of Rcan1 exon 4. These results indicate that GH activates c-JUN to affect the activity of calcineurin by the induction of Rcan1-4 in rat liver.


Assuntos
Hormônio do Crescimento/farmacologia , Peptídeos e Proteínas de Sinalização Intracelular/genética , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Animais , Regulação da Expressão Gênica/efeitos dos fármacos , Fosforilação/efeitos dos fármacos , RNA Mensageiro/genética , Ratos , Transdução de Sinais/efeitos dos fármacos
4.
PLoS One ; 15(4): e0231240, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32287299

RESUMO

OBJECTIVE: REG-O3 is a 24-aminoacid chimeric peptide combining a sequence derived from growth hormone (GH) and an analog of somatostatin (SST), molecules displaying cartilage repair and anti-inflammatory properties, respectively. This study aimed to investigate the disease-modifying osteoarthritis drug (DMOAD) potential of REG-O3 by analyzing its effect on pain, joint function and structure, upon injection into osteoarthritic rat knee joint. DESIGN: Osteoarthritis was induced in the right knee of mature male Lewis rats (n = 12/group) by surgical transection of the anterior cruciate ligament (ACLT) combined with partial medial meniscectomy (pMMx). Treatments were administered intra-articularly from fourteen days after surgery through three consecutive injections one week apart. The effect of REG-O3, solubilized in a liposomal solution and injected at either 5, 25 or 50 µg/50 µL, was compared to liposomal (LIP), dexamethasone and hyaluronic acid (HA) solutions. The study endpoints were the pain/function measured once a week throughout the entire study, and the joint structure evaluated eight weeks after surgery using OARSI score. RESULTS: ACLT/pMMx surgery induced a significant modification of weight bearing in all groups. When compared to liposomal solution, REG-O3 was able to significantly improve weight bearing as efficiently as dexamethasone and HA. REG-O3 (25 µg) was also able to significantly decrease OARSI histological global score as well as degeneration of both cartilage and matrix while the other treatments did not. CONCLUSION: This study provides evidence of a remarkable protecting effect of REG-O3 on pain/knee joint function and cartilage/matrix degradation in ACLT/pMMx model of rat osteoarthritis. REG-O3 thus displays an interesting profile as a DMOAD.


Assuntos
Lesões do Ligamento Cruzado Anterior/complicações , Anti-Inflamatórios não Esteroides/uso terapêutico , Cartilagem Articular/efeitos dos fármacos , Hormônio do Crescimento/uso terapêutico , Articulação do Joelho/efeitos dos fármacos , Osteoartrite do Joelho/tratamento farmacológico , Proteínas Recombinantes de Fusão/uso terapêutico , Somatostatina/uso terapêutico , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Cartilagem Articular/patologia , Modelos Animais de Doenças , Hormônio do Crescimento/farmacologia , Articulação do Joelho/patologia , Masculino , Osteoartrite do Joelho/etiologia , Ratos , Ratos Endogâmicos Lew , Proteínas Recombinantes de Fusão/farmacologia , Somatostatina/análogos & derivados , Somatostatina/farmacologia
5.
Life Sci ; 253: 117581, 2020 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-32209424

RESUMO

AIMS: Cisplatin (CDDP) is an effective antineoplastic agent, however, its serious nephrotoxicity limits therapeutic use. Human growth hormone (hGH) has proved antioxidant and anti-inflammatory activities. The present study aimed to investigate the nephroprotective effects of hGH against CDDP-induced nephrotoxicity and the mechanisms underlying this nephroprotection. MAIN METHODS: Male albino rats injected with CDDP (7 mg/kg) and nephrotoxicity indices, oxidative stress and inflammatory biomarkers (high mobility group box protein-1 (HMGB-1), soluble epoxide hydrolase (sEH), and nuclear factor-kappa B (NF-κB)) were assessed. Also, insulin-like growth factor-1 (IGF-1) and Nuclear factor-erythroid-2 (Nrf2)/heme oxygenase-1 (HO-1) pathway were assessed. KEY FINDINGS: hGH (1 mg/kg) improved kidney function and antioxidant systems and showed intact renal tubular epithelium. Cisplatin upregulated the HMGB-1/NF-κB and downregulated Nrf2/HO-1 pathways which were reversed by hGH and aligned with increased renal IGF-1 expression. Also, IGF-1/sEH crosstalk might be involved in hGH nephroprotection. Moreover, hGH downregulated HSP70 and caspase-3 expressions. SIGNIFICANCE: these results concluded that hGH can attenuate the inflammation and oxidative stress attained by CDDP probably through inhibition of Nrf2/HO-1 pathway. We also suggested that Keap1/Nrf2-mediated upregulation of the antioxidant HO-1 might inhibit HMGB-1/NF-κB signaling and thus provide the principal protection mechanism offered by hGH against CDDP-induced kidney injury.


Assuntos
Lesão Renal Aguda/prevenção & controle , Cisplatino/efeitos adversos , Hormônio do Crescimento/metabolismo , Heme Oxigenase-1/metabolismo , Fator de Crescimento Insulin-Like I/metabolismo , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Lesão Renal Aguda/induzido quimicamente , Lesão Renal Aguda/patologia , Animais , Anti-Infecciosos/efeitos adversos , Anti-Infecciosos/metabolismo , Antineoplásicos/efeitos adversos , Antineoplásicos/metabolismo , Antioxidantes/efeitos adversos , Antioxidantes/farmacologia , Caspase 3/metabolismo , Cisplatino/metabolismo , Modelos Animais de Doenças , Epóxido Hidrolases/metabolismo , Hormônio do Crescimento/farmacologia , Proteínas HMGB/metabolismo , Proteínas de Choque Térmico HSP70/metabolismo , Hormônio do Crescimento Humano , Humanos , Rim/efeitos dos fármacos , Rim/metabolismo , Rim/patologia , Masculino , NF-kappa B/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ratos , Transdução de Sinais
6.
Gen Comp Endocrinol ; 292: 113464, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32171745

RESUMO

Among the various ways that growth hormone (GH) underlies the growth physiology of teleost fishes, GH stimulates transport pathways that facilitate the absorption of nutrients across intestinal epithelia. The current study investigated the effects of GH on the gene expression of nutrient transporters in an omnivorous teleost, the Mozambique tilapia (Oreochromis mossambicus). We employed pituitary gland removal (hypophysectomy) and hormone replacement to assess whether GH directs the gene expression of the GH receptor (ghr2), the peptide transporters, pept1a, pept1b and pept2, the amino acid transporter, slc7a9, the Na+/glucose cotransporter, sglt1, the glucose transporter, glut2, and the myo-inositol transporter, smit2, in anterior, middle, and posterior intestine. ghr2 was predominantly expressed in posterior intestine, while pept1a, pept1b, slc7a9, sglt1, glut2, and smit2 exhibited the highest mRNA levels in anterior and/or middle intestine. While hypophysectomized tilapia exhibited diminished expression of ghr2, pept1a, pept1b, slc7a9, and glut2 compared with intact and sham-operated controls, only ghr2, pept1a, pept1b and glut2 levels were restored by GH replacement. Our findings indicate that GH supports growth, at least in part, by stimulating the gene expression of its cognate receptor and key nutrient transporters in the intestine.


Assuntos
Regulação da Expressão Gênica/efeitos dos fármacos , Hormônio do Crescimento/farmacologia , Intestinos/fisiologia , Proteínas de Membrana Transportadoras/metabolismo , Nutrientes , Tilápia/metabolismo , Animais , Proteínas de Peixes/genética , Proteínas de Peixes/metabolismo , Hipofisectomia , Intestinos/efeitos dos fármacos , Masculino , RNA Mensageiro/genética , Receptores da Somatotropina/metabolismo , Tilápia/genética
7.
Theriogenology ; 141: 180-185, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31550601

RESUMO

The aim of this research was to evaluate the effect of recombinant bovine somatotropin (bST) on pregnancy per artificial insemination (P/AI), cellular composition of the corpus luteum (CL) and endometrial gland morphometry. In Experiment 1, Nelore cows (n = 587) received a fixed-time artificial insemination (FTAI) protocol and, at insemination, received 0, 250 or 500 mg of bST subcutaneously (SC). In Experiment 2, Nelore cows (n = 243) received 0 or 500 mg of bST, SC, on D7 (D0 = day of FTAI). Blood samples were collected on D7 and D16 to measure progesterone (P4) concentrations. In Experiments 1 and 2, pregnancy diagnosis was performed 30 days after FTAI. In Experiment 3, Nelore heifers (n = 20) received a FTAI protocol, but were not inseminated, and on D0 (ovulation day), they received 0 (bST 0; n = 9) or 500 mg of bST (bST 500; n = 11), SC. The heifers were slaughtered on D15 (D0 = ovulation day), at which time the CL was evaluated for diameter, weight, a percentage of large (LLC) and small (SLC) luteal cells, and the concentration of progesterone in plasma measured. The number, perimeter and area of superficial and deep endometrial glands were evaluated. There was no difference in P/AI when bST was applied on D0 and D7. In Experiment 1, P/AI did not differ among treatments, with 59.28% (115/194), 58.38% (115/197) and 65.82% (129/196) for the bST 0, 250 and 500 treatments, respectively. In Experiment 2, P/AI did not differ between treatments, with 57.3% (71/124) and 60.5% (62/119) for the bST 0 and 500 treatments, respectively. Plasma progesterone concentrations on D16 was greater in the bST 500 (11.63 ±â€¯0.84 ng/mL) than bST 0 (9.83 ±â€¯0.88 ng/mL). In Experiment 3, there was no difference in ovarian diameter and weight, CL diameter, percentage of SLC, P4 concentrations and endometrial gland morphology. Heifers in the bST 500 treatment had heavier CL (3.11 ±â€¯0.32 vs. 2.25 ±â€¯0.20 g); however, the bST 0 treatment heifers had a greater percentage of LLC than did the bST 500 treatment (13.72 ±â€¯1.16% vs. 8.60 ±â€¯1.52). It was concluded that the doses of bST used in this study do not increase P/AI; however, they do cause changes in P4 concentration and the cellular composition of the CL.


Assuntos
Bovinos , Corpo Lúteo/citologia , Endométrio/anatomia & histologia , Hormônio do Crescimento/farmacologia , Inseminação Artificial/veterinária , Animais , Endométrio/fisiologia , Sincronização do Estro , Feminino , Hormônio do Crescimento/administração & dosagem , Gravidez , Proteínas Recombinantes
8.
Exp Clin Endocrinol Diabetes ; 128(2): 125-132, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30257265

RESUMO

BACKGROUND: Small for gestational age (SGA) due to intrauterine malnourishment is closely related to metabolic syndrome and type 2 diabetes mellitus. Growth Hormone (GH) treatment has been demonstrated to influence metabolic parameters and islet function of SGA individuals. The present study demonstrates the effects of early GH treatment on glucose tolerance and expression of pancreatic duodenal homeobox 1 (Pdx1) of SGA rats during adulthood. METHODS: SGA rat model was induced by restricting food intake during pregnancy. GH or normal saline was administered during postnatal days 21-35 of SGA rats and appropriate for gestational age (AGA) rats, respectively. RESULTS: In early adulthood (postnatal day 70), as compared to AGA rats, SGA rats showed: (1) decreased body weight; (2) increased postprandial blood glucose; and (3) down-regulated Pdx1 with increased histone deacetylase (HDAC) and down-regulated histone H3-lysine 4 methyltransferase SET7/9. Exogenous GH administration led to a restoration of body weight and normalized glucose tolerance due to an enhanced Pdx1 expression, accompanied by decreased HDAC and up-regulated SET7/9 in SGA rats in early adulthood. CONCLUSION: Our results demonstrate positive effects on glucose metabolism by an early and short GH treatment in SGA adulthood.


Assuntos
Peso Corporal/efeitos dos fármacos , Intolerância à Glucose/tratamento farmacológico , Intolerância à Glucose/metabolismo , Hormônio do Crescimento/farmacologia , Proteínas de Homeodomínio/efeitos dos fármacos , Proteínas de Homeodomínio/metabolismo , Recém-Nascido Pequeno para a Idade Gestacional/metabolismo , Transativadores/efeitos dos fármacos , Transativadores/metabolismo , Animais , Modelos Animais de Doenças , Feminino , Masculino , Gravidez , Ratos , Ratos Sprague-Dawley
10.
Lasers Med Sci ; 35(2): 345-354, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31201667

RESUMO

The aim of the present study was to verify the effects of muscular strength training and growth hormone (GH) supplementation on femoral bone tissue by Raman spectroscopy (Raman), dual-energy X-ray absorptiometry (DXA), and mechanical resistance (F-max) analysis. A total of 40 male Wistar animals, 60 days old, were used. The animals were distributed into four groups: control (C), control with GH (GHC), muscular strength training (T), and muscular strength training with GH (GHT). Blood samples were collected for the quantification of creatine kinase (CK-MB) and the femurs were removed for analysis by Raman, DXA, and F-max. A more pronounced increase in the bone mineral components was verified in the T group, for all the variables obtained by the Raman (calcium, phosphate, amide, and collagen). In addition, for animals submitted to GH supplementation, there was a reduction in the variable bone mineral density (BMD) obtained by the DXA (p < 0.05). Finally, the animals that received GH supplementation presented a higher F-max, but without statistical significance (p > 0.05). It was concluded that animals that received GH supplementation demonstrated a decrease in BMD. In addition, T alone was able to promote increased calcium, phosphate, amide, and collagen compounds in bone tissue.


Assuntos
Absorciometria de Fóton , Suplementos Nutricionais , Fêmur/fisiologia , Hormônio do Crescimento/farmacologia , Análise Espectral Raman , Animais , Fenômenos Biomecânicos , Peso Corporal/efeitos dos fármacos , Densidade Óssea/efeitos dos fármacos , Colágeno/metabolismo , Fêmur/efeitos dos fármacos , Masculino , Força Muscular , Ratos Wistar
11.
Sci Rep ; 9(1): 18995, 2019 12 12.
Artigo em Inglês | MEDLINE | ID: mdl-31831786

RESUMO

Growth hormone (GH) deficiency and loss of physical activity are common features in traumatic brain injury (TBI) patients that may contribute to bone loss. Therefore, we tested the hypothesis that GH treatment will rescue the hind limb unloading (UL)-induced skeletal deficit in TBI mice. Mild TBI was induced once per day for four consecutive days. UL (right hind limb) and treatment (3 mg/day GH or vehicle) began two weeks after the first TBI episode and lasted for four weeks. GH treatment increased femur BMD and lean body mass but decreased the % fat measured by DXA in the Control group. Micro-CT analysis revealed that the TBI, UL and TBI-UL groups showed reduced tibia trabecular (Tb) bone mass by 15%, 70%, and 75%, respectively compared to Control mice and that GH treatment significantly increased Tb. bone mass in all four groups. Vertebra also showed reduced Tb. bone mass in TBI, UL and TBI-UL groups. GH treatment increased vertebral Tb. bone mass in Control and UL groups but not in the TBI or TBI-UL group. GH treatment increased serum IGF-I levels similarly in TBI, UL and TBI-UL groups at day 14, suggesting the GH effect on liver IGF-I production was unaffected by skeletal UL. In contrast, GH effect on expression of ALP, IGFBP5 and axin2 in bone were compromised by UL. In conclusion, skeletal UL caused a greater Tb. bone deficit than mild TBI alone and that GH anabolic effects in the TBI and UL groups vary depending on the skeletal site.


Assuntos
Reabsorção Óssea/tratamento farmacológico , Reabsorção Óssea/etiologia , Lesões Encefálicas Traumáticas/complicações , Hormônio do Crescimento/uso terapêutico , Elevação dos Membros Posteriores , Absorciometria de Fóton , Adiposidade/efeitos dos fármacos , Fosfatase Alcalina/sangue , Animais , Índice de Massa Corporal , Peso Corporal/efeitos dos fármacos , Densidade Óssea/efeitos dos fármacos , Reabsorção Óssea/diagnóstico por imagem , Reabsorção Óssea/fisiopatologia , Osso Esponjoso/diagnóstico por imagem , Osso Esponjoso/efeitos dos fármacos , Osso Esponjoso/patologia , Osso Esponjoso/fisiopatologia , Feminino , Fêmur/efeitos dos fármacos , Fêmur/patologia , Fêmur/fisiopatologia , Regulação da Expressão Gênica/efeitos dos fármacos , Hormônio do Crescimento/farmacologia , Fator de Crescimento Insulin-Like I/metabolismo , Camundongos Endogâmicos C57BL , Osteogênese/efeitos dos fármacos , Tíbia/efeitos dos fármacos , Tíbia/patologia , Tíbia/fisiopatologia , Microtomografia por Raio-X
12.
Sci Rep ; 9(1): 19348, 2019 12 18.
Artigo em Inglês | MEDLINE | ID: mdl-31852980

RESUMO

Macrophages are an important component of the innate immune response. Priming and activation of macrophages is stimulated by cytokines (i.e IFNγ). However, growth hormone (GH) can also stimulate macrophage activation. Based on these observations, the goal of this work was to 1) to compare the transcriptome profile of macrophages activated in vitro with GH and IFNγ, and 2) to assess the impact of GH on key macrophage functional properties like reactive oxygen species (ROS) production and phagosomal proteolysis. To assess the global transcriptional and functional impact of GH on macrophage programming, bone marrow derived macrophages were treated with GH or IFNγ. Our data strongly support a potential link between GH, which wanes with age, and impaired macrophage function. The notable overlap of GH with IFNγ-induced pathways involved in innate immune sensing of pathogens and antimicrobial responses argue for an important role for GH in macrophage priming and maturation. By using functional assays that report on biochemical activities within the lumen of phagosomes, we have also shown that GH alters physiologically relevant processes such as ROS production and proteolysis. These changes could have far reaching impacts on antimicrobial capacity, signaling, and antigen presentation.


Assuntos
Reprogramação Celular/genética , Hormônio do Crescimento/farmacologia , Macrófagos/metabolismo , Transcriptoma/genética , Animais , Reprogramação Celular/efeitos dos fármacos , Perfilação da Expressão Gênica , Regulação da Expressão Gênica/efeitos dos fármacos , Interferon gama/farmacologia , Macrófagos/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Fagossomos/efeitos dos fármacos , Fagossomos/metabolismo , Análise de Componente Principal , Proteólise/efeitos dos fármacos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Análise de Sequência de RNA , Transcriptoma/efeitos dos fármacos , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo
13.
Int. j. morphol ; 37(4): 1416-1421, Dec. 2019. tab, graf
Artigo em Inglês | LILACS | ID: biblio-1040147

RESUMO

The indiscriminate use of anabolic steroids in gyms has been growing in a generalized way, among which, the most common is growth hormone (GH). In the short term GH may potentiate muscle growth, especially when taken in combination with resistance training. However, the effects of this hormone are not yet fully understood in the literature, especially in relation to collagen properties. The objective of this study was to evaluate the effect of the application of growth hormone (GH) and resistance training (RT) on the collagen properties of femoral bone tissue using Raman Spectroscopy. In this study 40 male rats were randomly distributed into four groups (n=10): control (C), control and GH application (GH), resistance training (T), and resistance training and GH application (GHT). The training consisted of four series of 10 water jumps, performed three times a week, with an overload corresponding to 50 % of body weight and duration of four weeks. GH was applied at a dosage of 0.2 IU/Kg (0.067 mg/kg) to each animal, three times a week, every other day. The animals were euthanized and the right femurs were collected for analysis of bone structure. Raman spectroscopy (RS) was used to observe the following compounds from their respective bands: type I collagen (662 cm-1), amide III (1243 cm-1), proteins including type I collagen (1278 cm-1), woven collagen (1322 cm-1), association of collagen, phospholipids, nucleic acid, and phosphate (1330 cm-1), and collagen and protein deformation (1448 cm-1). The results demonstrated an increase in the collagen properties in all analyzed variables, however, the T group presented a statistically significant difference (p<0.05). It is possible to conclude that isolated physical training was shown to be more efficient than when combined with the application of GH to increase the collagen properties of the femoral bone tissue.


El uso indiscriminado de anabolizantes en los gimnasios ha aumentado de forma generalizada, entre éstos la hormona de crecimiento (HC) es una de las más utilizadas, y a corto plazo puede potencializar el crecimiento muscular, principalmente cuando es realizado en combinación con el entrenamiento de fuerza. Sin embargo, los efectos de esta hormona aún no están totalmente esclarecidos en la literatura, especialmente en relación a las propiedades colágenas. El objetivo del estudio fue evaluar el efecto de la aplicación del HC y entrenamiento de fuerza (E) en las propiedades colágenas del tejido óseo femoral a partir de la utilización de la espectroscopía Raman. Se usaron 40 ratas Wistar distribuidos en cuatro grupos (n=10): control (C), control y aplicación del HC (HCC), entrenamiento de fuerza (E) y entrenamiento de fuerza y aplicación del HC (THC). El entrenamiento fue compuesto por cuatro series de 10 saltos acuáticos, realizados tres veces por semana, con sobrecarga correspondiente a 50 % del peso corporal y duración de cuatro semanas. El HC fue aplicado en una dosificación de 0,2 UI/Kg (0,067 mg/kg) en cada animal, tres veces por semana, en días no consecutivos. Los animales fueran eutanasiados y se retiró el fémur derecho para realización del análisis de la estructura ósea. La espectroscopía Raman (ER) fue utilizada para observar los siguientes compuestos a partir de las respectivas bandas: colágeno tipo I (662 cm-1), amida III (1243 cm1), proteínas, incluido colágeno tipo I (1278 cm-1), colágeno retorcido (1322 cm-1), asociación de colágeno, fosfolípidos, ácidos nucleicos y fosfato (1330 cm-1), deformación de colágeno y proteína (1448 cm-1). Hubo aumento en las propiedades colágenas en todas las variables analizadas, sin embargo, solamente el grupo E demostró una diferencia estadísticamente significativa (p<0,05). En conclusión, para el aumento de las propiedades colágenas del tejido óseo femoral, el entrenamiento físico aislado es más eficiente que el entrenamiento combinado con el uso de HC.


Assuntos
Animais , Masculino , Ratos , Resistência Física/fisiologia , Hormônio do Crescimento/farmacologia , Fêmur/efeitos dos fármacos , Fêmur/fisiologia , Hormônio do Crescimento/administração & dosagem , Exercício Físico/fisiologia , Colágeno/efeitos dos fármacos , Ratos Wistar , Microscopia/métodos
14.
J Neuroendocrinol ; 31(11): e12804, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31630448

RESUMO

Colour vision relies on retinal photoreceptors that express a different predominant visual pigment protein (opsin). In several vertebrates, the primary opsin expressed by a photoreceptor can change throughout ontogeny, although the molecular factors that influence such regulation are poorly understood. One of these factors is thyroid hormone which, together with its receptors, modulates opsin expression in the retinas of multiple vertebrates including rodents and salmonid fishes. In the latter, thyroid hormone induces a switch in opsin expression from SWS1 (ultraviolet light sensitive) to SWS2 (short wavelength or blue light sensitive) in the single cone photoreceptors of the retina. The actions of other hormones on opsin expression have not been investigated. In the present study, we used a transgenic strain of coho salmon (Oncorhynchus kitsutch) with enhanced levels of circulating growth hormone compared to that of wild siblings to assess the effects of this hormone on the SWS1 to SWS2 opsin switch. Transgenic fish showed a developmentally accelerated opsin switch compared to size-matched controls as assessed by immunohistological and in situ hybridisation labelling of photoreceptors and by quantification of transcripts using quantitative polymerase chain reaction. This accelerated switch led to a different spectral sensitivity maximum, under a middle to long wavelength adapting background, from ultraviolet (λmax  ~ 380 nm) in controls to short wavelengths (λmax  ~ 430 nm) in transgenics, demonstrating altered colour vision. The effects of growth hormone over-expression were independent of circulating levels of thyroid hormone (triiodothyronine), the hormone typically associated with opsin switches in vertebrates.


Assuntos
Hormônio do Crescimento/fisiologia , Oncorhynchus kisutch , Opsinas/genética , Retina/metabolismo , Animais , Animais Geneticamente Modificados , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos da radiação , Hormônio do Crescimento/sangue , Hormônio do Crescimento/genética , Hormônio do Crescimento/farmacologia , Luz , Oncorhynchus kisutch/genética , Oncorhynchus kisutch/metabolismo , Opsinas/metabolismo , Retina/efeitos dos fármacos , Células Fotorreceptoras Retinianas Cones/efeitos dos fármacos , Células Fotorreceptoras Retinianas Cones/metabolismo , Opsinas de Bastonetes/genética , Opsinas de Bastonetes/metabolismo , Salmonidae/genética , Salmonidae/metabolismo , Hormônios Tireóideos/sangue
15.
J Biol Chem ; 294(44): 16109-16122, 2019 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-31511328

RESUMO

Growth hormone (GH) plays a significant role in normal renal function and overactive GH signaling has been implicated in proteinuria in diabetes and acromegaly. Previous results have shown that the glomerular podocytes, which play an essential role in renal filtration, express the GH receptor, suggesting the direct action of GH on these cells. However, the exact mechanism and the downstream pathways by which excess GH leads to diabetic nephropathy is not established. In the present article, using immortalized human podocytes in vitro and a mouse model in vivo, we show that excess GH activates Notch1 signaling in a γ-secretase-dependent manner. Pharmacological inhibition of Notch1 by γ-secretase inhibitor DAPT (N-[N-(3,5-Difluorophenacetyl)-l-alanyl]-S-phenyl glycine t-butylester) abrogates GH-induced epithelial to mesenchymal transition (EMT) and is associated with a reduction in podocyte loss. More importantly, our results show that DAPT treatment blocks cytokine release and prevents glomerular fibrosis, all of which are induced by excess GH. Furthermore, DAPT prevented glomerular basement membrane thickening and proteinuria induced by excess GH. Finally, using kidney biopsy sections from people with diabetic nephropathy, we show that Notch signaling is indeed up-regulated in such settings. All these results confirm that excess GH induces Notch1 signaling in podocytes, which contributes to proteinuria through EMT as well as renal fibrosis. Our studies highlight the potential application of γ-secretase inhibitors as a therapeutic target in people with diabetic nephropathy.


Assuntos
Nefropatias Diabéticas/metabolismo , Hormônio do Crescimento/farmacologia , Podócitos/metabolismo , Proteinúria/metabolismo , Receptor Notch1/metabolismo , Transdução de Sinais , Animais , Células Cultivadas , Citocinas/metabolismo , Nefropatias Diabéticas/tratamento farmacológico , Dipeptídeos/farmacologia , Dipeptídeos/uso terapêutico , Transição Epitelial-Mesenquimal , Humanos , Masculino , Camundongos , Podócitos/efeitos dos fármacos , Podócitos/patologia , Proteinúria/tratamento farmacológico , Receptor Notch1/antagonistas & inibidores , Receptor Notch1/genética
16.
Int J Mol Sci ; 20(18)2019 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-31491959

RESUMO

Growth hormone secretagogues (GHS) are a family of synthetic molecules, first discovered in the late 1970s for their ability to stimulate growth hormone (GH) release. Many effects of GHS are mediated by binding to GHS-R1a, the receptor for the endogenous hormone ghrelin, a 28-amino acid peptide isolated from the stomach. Besides endocrine functions, both ghrelin and GHS are endowed with some relevant extraendocrine properties, including stimulation of food intake, anticonvulsant and anti-inflammatory effects, and protection of muscle tissue in different pathological conditions. In particular, ghrelin and GHS inhibit cardiomyocyte and endothelial cell apoptosis and improve cardiac left ventricular function during ischemia-reperfusion injury. Moreover, in a model of cisplatin-induced cachexia, GHS protect skeletal muscle from mitochondrial damage and improve lean mass recovery. Most of these effects are mediated by GHS ability to preserve intracellular Ca2+ homeostasis. In this review, we address the muscle-specific protective effects of GHS mediated by Ca2+ regulation, but also highlight recent findings of their therapeutic potential in pathological conditions characterized by skeletal or cardiac muscle impairment.


Assuntos
Sinalização do Cálcio/efeitos dos fármacos , Hormônio do Crescimento/farmacologia , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , Secretagogos/farmacologia , Animais , Humanos
17.
Int J Mol Sci ; 20(18)2019 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-31509934

RESUMO

In addition to its role as an endocrine messenger, growth hormone (GH) also acts as a neurotrophic factor in the central nervous system (CNS), whose effects are involved in neuroprotection, axonal growth, and synaptogenic modulation. An increasing amount of clinical evidence shows a beneficial effect of GH treatment in patients with brain trauma, stroke, spinal cord injury, impaired cognitive function, and neurodegenerative processes. In response to injury, Müller cells transdifferentiate into neural progenitors and proliferate, which constitutes an early regenerative process in the chicken retina. In this work, we studied the long-term protective effect of GH after causing severe excitotoxic damage in the retina. Thus, an acute neural injury was induced via the intravitreal injection of kainic acid (KA, 20 µg), which was followed by chronic administration of GH (10 injections [300 ng] over 21 days). Damage provoked a severe disruption of several retinal layers. However, in KA-damaged retinas treated with GH, we observed a significant restoration of the inner plexiform layer (IPL, 2.4-fold) and inner nuclear layer (INL, 1.5-fold) thickness and a general improvement of the retinal structure. In addition, we also observed an increase in the expression of several genes involved in important regenerative pathways, including: synaptogenic markers (DLG1, NRXN1, GAP43); glutamate receptor subunits (NR1 and GRIK4); pro-survival factors (BDNF, Bcl-2 and TNF-R2); and Notch signaling proteins (Notch1 and Hes5). Interestingly, Müller cell transdifferentiation markers (Sox2 and FGF2) were upregulated by this long-term chronic GH treatment. These results are consistent with a significant increase in the number of BrdU-positive cells observed in the KA-damaged retina, which was induced by GH administration. Our data suggest that GH is able to facilitate the early proliferative response of the injured retina and enhance the regeneration of neurite interconnections.


Assuntos
Hormônio do Crescimento/farmacologia , Ácido Caínico/toxicidade , Regeneração/efeitos dos fármacos , Retina/efeitos dos fármacos , Animais , Animais Recém-Nascidos , Fator Neurotrófico Derivado do Encéfalo/genética , Embrião de Galinha , Galinhas , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Neurogênese/efeitos dos fármacos , Neurogênese/genética , Neurogênese/fisiologia , Fármacos Neuroprotetores/farmacologia , Neurotoxinas/toxicidade , Receptor Notch1/genética , Regeneração/genética , Regeneração/fisiologia , Retina/metabolismo , Retina/fisiopatologia , Fatores de Transcrição SOXB1/genética
18.
Domest Anim Endocrinol ; 69: 84-95, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31382237

RESUMO

This study was undertaken to examine the effect of GH treatment during a pause in laying on (1) ovarian follicle formation, growth (folliculogenesis), and atresia; (2) follicle cell proliferation and apoptosis; and (3) mRNA expression of selected yolk-specific proteins in the chicken liver. A pause in egg laying was induced by food deprivation for 5 d, followed by feeding every other day, and then feeding daily from day 10 onward. Birds were divided into 3 groups: control (n = 18) fed ad libitum, subjected to a pause in laying (n = 18), and subjected to a pause in laying and injected every day with 200 µg/kg BW of chicken GH (chGH; n = 18). The liver, ovarian stroma, and follicles were isolated from the hens of each group on days 6 (ovary regression), 13 (ovary recrudescence), and 17 or 20 (ovary rejuvenated) of the experiment. The results showed that injection of chGH during fasting (1) increased the number of follicles <1 mm and proliferating cell nuclear antigen (PCNA)-positive (proliferating) cells in these follicles; (2) attenuated the expression of PCNA and survivin mRNA in the white follicles and the activity of caspases 3, 8, and 9 in the stroma and white follicles; (3) intensified the atresia of yellow hierarchical follicles; and (4) deepened the effect of starvation on egg yolk gene expression concomitantly with considerably increased IGF-1 transcription levels in the liver (P < 0.05 to P < 0.001). Prolongation of chGH injections into the refeeding period did not exert pronounced effects on the examined parameters. In summary, the results provide evidence that GH promotes the formation and development of prehierarchical follicles in the hen ovary during a pause in laying by regulating cell proliferation and apoptosis. Alterations in cell proliferation- and apoptosis-related gene expression or enzyme activity in ovarian follicles as well as the expression of egg yolk proteins in the liver after chGH treatment strongly suggest that this hormone is involved in determining the rate of regression and rejuvenation of the chicken ovary during a pause in laying.


Assuntos
Galinhas , Privação de Alimentos , Hormônio do Crescimento/farmacologia , Ovário/efeitos dos fármacos , Oviposição/fisiologia , Animais , Apoptose , Caspases/metabolismo , Proliferação de Células , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Ovário/citologia , Ovário/fisiologia , RNA/genética , RNA/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa/veterinária
19.
Nutrients ; 11(8)2019 Aug 17.
Artigo em Inglês | MEDLINE | ID: mdl-31426533

RESUMO

Growth hormone (GH) and glutamine (Gln) stimulate the growth of the intestinal mucosa. GH activates the proliferation of intestinal stem cells (ISCs), enhances the formation of crypt organoids, increases ISC stemness markers in the intestinal organoids, and drives the differentiation of ISCs into Paneth cells and enterocytes. Gln enhances the proliferation of ISCs and increases crypt organoid formation; however, it mainly acts on the post-proliferation activity of ISCs to maintain the stability of crypt organoids and the intestinal mucosa, as well as to stimulate the differentiation of ISCs into goblet cells and possibly Paneth cells and enteroendocrine cells. Since GH and Gln have differential effects on ISCs. Their use in combination may have synergistic effects on ISCs. In this review, we summarize the evidence of the actions of GH and/or Gln on crypt cells and ISCs in the literature. Overall, most studies demonstrated that GH and Gln in combination exerted synergistic effects to activate the proliferation of crypt cells and ISCs and enhance crypt organoid formation and mucosal growth. This treatment influenced the proliferation of ISCs to a similar degree as GH treatment alone and the differentiation of ISCs to a similar degree as Gln treatment alone.


Assuntos
Glutamina/farmacologia , Hormônio do Crescimento/farmacologia , Mucosa Intestinal/efeitos dos fármacos , Células-Tronco/efeitos dos fármacos , Diferenciação Celular , Proliferação de Células , Sinergismo Farmacológico , Humanos , Mucosa Intestinal/citologia , Mucosa Intestinal/crescimento & desenvolvimento , Organoides/efeitos dos fármacos , Organoides/crescimento & desenvolvimento , Células-Tronco/fisiologia
20.
FASEB J ; 33(11): 11909-11924, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31366244

RESUMO

Growth hormone (GH) is secreted during hypoglycemia, and GH-responsive neurons are found in brain areas containing glucose-sensing neurons that regulate the counter-regulatory response (CRR). However, whether GH modulates the CRR to hypoglycemia via specific neuronal populations is currently unknown. Mice carrying ablation of GH receptor (GHR) either in leptin receptor (LepR)- or steroidogenic factor-1 (SF1)-expressing cells were studied. We also investigated the importance of signal transducer and activator of transcription 5 (STAT5) signaling in SF1 cells for the CRR. GHR ablation in LepR cells led to impaired capacity to recover from insulin-induced hypoglycemia and to a blunted CRR caused by 2-deoxy-d-glucose (2DG) administration. GHR inactivation in SF1 cells, which include ventromedial hypothalamic neurons, also attenuated the CRR. The reduced CRR was prevented by parasympathetic blockers. Additionally, infusion of 2DG produced an abnormal hyperactivity of parasympathetic preganglionic neurons, whereas the 2DG-induced activation of anterior bed nucleus of the stria terminalis neurons was reduced in mice without GHR in SF1 cells. Mice carrying ablation of Stat5a/b genes in SF1 cells showed no defects in the CRR. In summary, GHR expression in SF1 cells is required for a normal CRR, and these effects are largely independent of STAT5 pathway.-Furigo, I. C., de Souza, G. O., Teixeira, P. D. S., Guadagnini, D., Frazão, R., List, E. O., Kopchick, J. J., Prada, P. O., Donato, J., Jr. Growth hormone enhances the recovery of hypoglycemia via ventromedial hypothalamic neurons.


Assuntos
Hormônio do Crescimento/farmacologia , Hipoglicemia/tratamento farmacológico , Hipotálamo/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Recuperação de Função Fisiológica/efeitos dos fármacos , Animais , Desoxiglucose/farmacologia , Hipoglicemia/fisiopatologia , Hipotálamo/citologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neurônios/metabolismo , Neurônios/fisiologia , Receptores para Leptina/genética , Receptores para Leptina/metabolismo , Receptores da Somatotropina/genética , Receptores da Somatotropina/metabolismo , Fator de Transcrição STAT5/genética , Fator de Transcrição STAT5/metabolismo , Transdução de Sinais/efeitos dos fármacos , Fator Esteroidogênico 1/genética , Fator Esteroidogênico 1/metabolismo
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