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1.
Adv Clin Exp Med ; 29(4): 499-504, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32356415

RESUMO

BACKGROUND: The pathogenesis of classical galactosemia, a rare metabolic disorder associated with developmental complications in neonates and children due to inherited deficiency of galactose-1-phosphate (Gal-1-P) uridylyltransferase (GALT), is known to be mediated by elevated Gal-1-P levels and involves a cascade of cytokines, reactive oxygen species (ROS) and growth factors. OBJECTIVES: To examine ex vivo the effect of Gal-1-P on the mitogenic activity of different growth factors, particularly insulin-like growth factor-1 (IGF-1), known to regulate growth and development from the fetal stage to adulthood. MATERIAL AND METHODS: Fibroblasts derived from the foreskin of 3-8-day-old healthy neonates were cultured for 1-14 days with 0-20 mM galactose or 0-10 mM Gal-1-P and then stimulated with 5% fetal bovine serum (FBS) or 50 ng/mL of platelet-derived growth factor (PDGF) or fibroblast growth factor (FGF) or IGF-1 for 24 h. DNA synthesis was measured and protein expression of PDGFR, FGFR and IGF-1R was assessed with western blotting. RESULTS: Supra-physiological concentrations of galactose significantly decreased FBSand IGF-1-induced BrdU incorporation. The presence of Gal-1-P (5-10 mM) in culture medium for 7-14 days significantly (p < 0.01) decreased IGF-1-, PDGFand FBS-stimulated DNA synthesis. While treatment with Gal-1-P selectively and significantly (p < 0.01) reduced the protein expression of IGF-1 receptor, galactose treatment did not have any marked effect on examined growth factor receptors. CONCLUSIONS: This study demonstrates that Gal-1-P impairs IGF-1 activity through IGF-1-receptor impairment, thereby providing a new insight into the molecular mechanisms of galactosemia pathogenesis.


Assuntos
Fibroblastos/efeitos dos fármacos , Galactosemias/patologia , Galactosefosfatos/metabolismo , Fator de Crescimento Insulin-Like I/metabolismo , Células Cultivadas , Fibroblastos/metabolismo , Galactosemias/sangue , Galactosemias/metabolismo , Humanos , Recém-Nascido , Fator de Crescimento Insulin-Like I/genética
2.
Anticancer Res ; 40(4): 1915-1920, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32234880

RESUMO

BACKGROUND/AIM: New anticancer drugs are usually tested on cancer cells in culture in a standard medium. We stimulated immune polynuclear cells by lipopolysaccharides to obtain an enriched medium (EM) containing inflammatory cytokines more closely reflecting the tumor microenvironment and tested a rhenium-diselenium (Re-diSe) drug in this new model. Concentrations of cytokines were compared with a control medium (CM). MATERIALS AND METHODS: Human-derived breast cancer cells were grown in culture either in CM or EM with or without Re-diSe. Assays of tumor necrosis factor alpha (TNFα), interleukin 6 (IL6), intereukin 1 beta (IL1ß), transforming growth factor-beta (TGFß), insulin growth factor 1 (IGF1) and vascular epidermal growth factor A (VEGFA) were performed by enzyme-linked immunosorbent assays. The production of reactive oxygen species (ROS) was determined by 2,7-dichlorofluorescein test. The cell growth was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide tests. RESULTS: Concentrations of TNFα, IL6 and Il1ß were observed to be significantly higher in EM than in CM. There was no difference for TGFß, IGF1 and VEGFA. The cells were sensitive to Re-diSe, with reduced concentrations of TGFß, IGF1, VEGFA and ROS, but the half-maximal inhibitory concentration was significantly higher in EM than in CM. CONCLUSION: The efficacy of the Re-diSe drug was confirmed in this model of aggressive cancer.


Assuntos
Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Rênio/farmacologia , Selênio/farmacologia , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Proliferação de Células/efeitos dos fármacos , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Fator de Crescimento Insulin-Like I/genética , Interleucina-1beta/genética , Interleucina-6/genética , Lipopolissacarídeos/farmacologia , Cultura Primária de Células , Espécies Reativas de Oxigênio , Fator de Crescimento Transformador beta/genética , Microambiente Tumoral/efeitos dos fármacos , Fator A de Crescimento do Endotélio Vascular/genética
3.
Clin Sci (Lond) ; 134(8): 961-984, 2020 04 30.
Artigo em Inglês | MEDLINE | ID: mdl-32313958

RESUMO

Maternal obesity is associated with pregnancy complications and increases the risk for the infant to develop obesity, diabetes and cardiovascular disease later in life. However, the mechanisms linking the maternal obesogenic environment to adverse short- and long-term outcomes remain poorly understood. As compared with pregnant women with normal BMI, women entering pregnancy obese have more pronounced insulin resistance, higher circulating plasma insulin, leptin, IGF-1, lipids and possibly proinflammatory cytokines and lower plasma adiponectin. Importantly, the changes in maternal levels of nutrients, growth factors and hormones in maternal obesity modulate placental function. For example, high insulin, leptin, IGF-1 and low adiponectin in obese pregnant women activate mTOR signaling in the placenta, promoting protein synthesis, mitochondrial function and nutrient transport. These changes are believed to increase fetal nutrient supply and contribute to fetal overgrowth and/or adiposity in offspring, which increases the risk to develop disease later in life. However, the majority of obese women give birth to normal weight infants and these pregnancies are also associated with activation of inflammatory signaling pathways, oxidative stress, decreased oxidative phosphorylation and lipid accumulation in the placenta. Recent bioinformatics approaches have expanded our understanding of how maternal obesity affects the placenta; however, the link between changes in placental function and adverse outcomes in obese women giving birth to normal sized infants is unclear. Interventions that specifically target placental function, such as activation of placental adiponectin receptors, may prevent the transmission of metabolic disease from obese women to the next generation.


Assuntos
Obesidade Materna/metabolismo , Placenta/metabolismo , Complicações na Gravidez/metabolismo , Adiponectina/genética , Adiponectina/metabolismo , Adiposidade , Animais , Feminino , Humanos , Fator de Crescimento Insulin-Like I/genética , Fator de Crescimento Insulin-Like I/metabolismo , Obesidade Materna/genética , Obesidade Materna/psicologia , Gravidez , Complicações na Gravidez/genética , Complicações na Gravidez/fisiopatologia
4.
FASEB J ; 34(1): 555-570, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31914652

RESUMO

Muscle wasting, or muscle atrophy, can occur with age, injury, and disease; it affects the quality of life and complicates treatment. Insulin-like growth factor 1 (IGF1) is a key positive regulator of muscle mass. The IGF1/Igf1 gene encodes multiple protein isoforms that differ in tissue expression, potency, and function, particularly in cellular proliferation and differentiation, as well as in systemic versus localized signaling. Genome engineering is a novel strategy for increasing gene expression and has the potential to recapitulate the diverse biology seen in IGF1 signaling through the overexpression of multiple IGF1 isoforms. Using a CRISPR-Cas9 gene activation approach, we showed that the expression of multiple IGF1 or Igf1 mRNA variants can be increased in human and mouse skeletal muscle myoblast cell lines using a single-guide RNA (sgRNA). We found increased IGF1 protein levels in the cell culture media and increased cellular phosphorylation of AKT1, the main effector of IGF1 signaling. We also showed that the expression of Class 1 or Class 2 mRNA variants can be selectively increased by changing the sgRNA target location. The expression of multiple IGF1 or Igf1 mRNA transcript variants in human and mouse skeletal muscle myoblasts promoted myotube differentiation and prevented dexamethasone-induced atrophy in myotubes in vitro. Our findings suggest that this novel approach for enhancing IGF1 signaling has potential therapeutic applications for treating skeletal muscle atrophy.


Assuntos
Sistemas CRISPR-Cas , Diferenciação Celular , Fator de Crescimento Insulin-Like I/metabolismo , Músculo Esquelético/citologia , Atrofia Muscular/patologia , Mioblastos/citologia , Ativação Transcricional , Animais , Anti-Inflamatórios/farmacologia , Sequência de Bases , Proliferação de Células , Células Cultivadas , Dexametasona/farmacologia , Humanos , Fator de Crescimento Insulin-Like I/genética , Camundongos , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , Atrofia Muscular/induzido quimicamente , Atrofia Muscular/metabolismo , Mioblastos/efeitos dos fármacos , Mioblastos/metabolismo , Fosforilação , Isoformas de Proteínas , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Homologia de Sequência , Transdução de Sinais
5.
Sci Rep ; 10(1): 1433, 2020 01 29.
Artigo em Inglês | MEDLINE | ID: mdl-31996736

RESUMO

Variations in the human genome have been found to be an essential factor that affects susceptibility to Alzheimer's disease. Genome-wide association studies (GWAS) have identified genetic loci that significantly contribute to the risk of Alzheimers. The availability of genetic data, coupled with brain imaging technologies have opened the door for further discoveries, by using data integration methodologies and new study designs. Although methods have been proposed for integrating image characteristics and genetic information for studying Alzheimers, the measurement of disease is often taken at a single time point, therefore, not allowing the disease progression to be taken into consideration. In longitudinal settings, we analyzed neuroimaging and single nucleotide polymorphism datasets obtained from the Alzheimer's Disease Neuroimaging Initiative for three clinical stages of the disease, including healthy control, early mild cognitive impairment and Alzheimer's disease subjects. We conducted a GWAS regressing the absolute change of global connectivity metrics on the genetic variants, and used the GWAS summary statistics to compute the gene and pathway scores. We observed significant associations between the change in structural brain connectivity defined by tractography and genes, which have previously been reported to biologically manipulate the risk and progression of certain neurodegenerative disorders, including Alzheimer's disease.


Assuntos
Doença de Alzheimer/genética , Encéfalo/fisiologia , Doença de Alzheimer/diagnóstico , Encéfalo/diagnóstico por imagem , Conectoma , Progressão da Doença , Ontologia Genética , Redes Reguladoras de Genes , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Fator de Crescimento Insulin-Like I/genética , Fenótipo , Polimorfismo de Nucleotídeo Único , Receptores Acoplados a Proteínas-G/genética , Receptores de Peptídeos/genética , Transmissão Sináptica
6.
Am J Physiol Lung Cell Mol Physiol ; 318(3): L549-L561, 2020 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-31913647

RESUMO

Prenatal smoke exposure (PSE) is associated with reduced birth weight, impaired fetal development, and increased risk for diseases later in life. Changes in DNA methylation may be involved, as multiple large-scale epigenome-wide association studies showed that PSE is robustly associated with DNA methylation changes in blood among offspring in early life. Insulin-like growth factor-1 (IGF1) is important in growth, differentiation, and repair processes after injury. However, no studies investigated the organ-specific persistence of PSE-induced methylation change of Igf1 into adulthood. Based on our previous studies on the PSE effect on Igf1 promoter methylation in fetal and neonatal mouse offspring, we now have extended our studies to adulthood. Our data show that basal Igf1 promoter methylation generally increased in the lung but decreased in the liver (except for 2 persistent CpG sites in both organs) across three different developmental stages. PSE changed Igf1 promoter methylation in all three developmental stages, which was organ and sex specific. The PSE effect was less pronounced in adult offspring compared with the fetal and neonatal stages. In addition, the PSE effect in the adult stage was more pronounced in the lung compared with the liver. For most CpG sites, an inverse correlation was found for promoter methylation and mRNA expression when the data of all three stages were combined. This was more prominent in the liver. Our findings provide additional evidence for sex- and organ-dependent prenatal programming, which supports the developmental origins of health and disease (DOHaD) hypothesis.


Assuntos
Metilação de DNA , Retardo do Crescimento Fetal/patologia , Regulação da Expressão Gênica no Desenvolvimento , Fator de Crescimento Insulin-Like I/genética , Efeitos Tardios da Exposição Pré-Natal/patologia , Regiões Promotoras Genéticas , Fumaça/efeitos adversos , Animais , Animais Recém-Nascidos , Epigênese Genética , Feminino , Retardo do Crescimento Fetal/etiologia , Retardo do Crescimento Fetal/metabolismo , Masculino , Camundongos , Especificidade de Órgãos , Gravidez , Efeitos Tardios da Exposição Pré-Natal/etiologia , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Fatores Sexuais
7.
Biochim Biophys Acta Mol Cell Res ; 1867(2): 118563, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31666191

RESUMO

Skeletal muscle secretes biologically active proteins that contribute to muscle hypertrophy in response to either exercise or dietary intake. The identification of skeletal muscle-secreted proteins that induces hypertrophy can provide critical information regarding skeletal muscle health. Dietary provitamin A, ß-carotene, induces hypertrophy of the soleus muscle in mice. Here, we hypothesized that skeletal muscle produces hypertrophy-inducible secretory proteins via dietary ß-carotene. Knockdown of retinoic acid receptor (RAR) γ inhibited the ß-carotene-induced increase soleus muscle mass in mice. Using RNA sequencing, bioinformatic analyses, and literature searching, we predicted transglutaminase 2 (TG2) to be an all-trans retinoic acid (ATRA)-induced secretory protein in cultured C2C12 myotubes. Tg2 mRNA expression increased in ATRA- or ß-carotene-stimulated myotubes and in the soleus muscle of ß-carotene-treated mice. Knockdown of RARγ inhibited ß-carotene-increased mRNA expression of Tg2 in the soleus muscle. ATRA increased endogenous TG2 levels in conditioned medium from myotubes. Extracellular TG2 promoted the phosphorylation of Akt, mechanistic target of rapamycin (mTOR), and ribosomal p70 S6 kinase (p70S6K), and inhibitors of mTOR, phosphatidylinositol 3-kinase, and Src (rapamycin, LY294002, and Src I1, respectively) inhibited TG2-increased phosphorylation of mTOR and p70S6K. Furthermore, extracellular TG2 promoted protein synthesis and hypertrophy in myotubes. TG2 mutant lacking transglutaminase activity exerted the same effects as wild-type TG2. Knockdown of G protein-coupled receptor 56 (GPR56) inhibited the effects of TG2 on mTOR signaling, protein synthesis, and hypertrophy. These results indicated that TG2 expression was upregulated through ATRA-mediated RARγ and that extracellular TG2 induced myotube hypertrophy by activating mTOR signaling-mediated protein synthesis through GPR56, independent of transglutaminase activity.


Assuntos
Proteínas de Ligação ao GTP/metabolismo , Receptores Acoplados a Proteínas-G/metabolismo , Transglutaminases/metabolismo , Animais , Crescimento Celular/efeitos dos fármacos , Linhagem Celular , Proteínas de Ligação ao GTP/genética , Fator de Crescimento Insulin-Like I/genética , Fator de Crescimento Insulin-Like I/metabolismo , Camundongos , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , Mioblastos/citologia , Mioblastos/metabolismo , Fosforilação/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Receptores Acoplados a Proteínas-G/antagonistas & inibidores , Receptores Acoplados a Proteínas-G/genética , Receptores do Ácido Retinoico/antagonistas & inibidores , Receptores do Ácido Retinoico/genética , Receptores do Ácido Retinoico/metabolismo , Receptor alfa de Ácido Retinoico/antagonistas & inibidores , Receptor alfa de Ácido Retinoico/genética , Receptor alfa de Ácido Retinoico/metabolismo , Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo , Transglutaminases/genética , Tretinoína/farmacologia , beta Caroteno/administração & dosagem , beta Caroteno/farmacologia
8.
Toxicol Lett ; 321: 44-53, 2020 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-31811911

RESUMO

This study was aimed to investigate the effect of prenatal ethanol exposure (PEE) on the susceptibility of offspring rats to glomerulosclerosis and to explore the mechanism. Pregnant Wistar rats were intragastrically administered ethanol (4g/kg·d) from gestational day (GD) 9 to GD 20, and the control group was given equal volume of normal saline. The offspring rats were all fed with high-fat diet after weaning, and were sacrificed at postnatal week 24 (PW24). The results revealed that the adult offspring kidneys in the male and female PEE groups exhibited higher glomerulosclerosis index and interstitial fibrosis index compared with the high-fat diet control groups, accompanied by elevated serum creatinine level. The protein expression of Nephrin and WT1, which were the marker genes of podocytes, was significantly decreased, whereas the protein expression of desmin and α-SMA, the marker genes of mesenchymal cells, was remarked enhanced in the male and female PEE groups. Compared with the high-fat diet control groups, the mRNA and protein expressions of renal angiotensin II receptor type 2 (AT2R) were decreased in the male PEE group, but increased in the female PEE group. PEE increased the mRNA and protein expressions of glucocorticoid (GC) activation system and inhibited the expression of insulin-like growth factor 1 (IGF1) signaling pathway in male offspring kidney; on the contrary, in female offspring kidney, PEE inhibited the mRNA and protein expression of glucocorticoid activation system and increased the expression of IGF1 signaling pathway. Taken together, PEE increased the susceptibility of the adult offspring to glomerulosclerosis, and the programming of renal AT2R or GC-IGF1 is respectively involved in the toxicity of PEE to the male or female offspring.


Assuntos
Dieta Hiperlipídica , Etanol/toxicidade , Glomerulonefrite/etiologia , Glomérulos Renais/efeitos dos fármacos , Efeitos Tardios da Exposição Pré-Natal , Transdução de Sinais/efeitos dos fármacos , Animais , Feminino , Fibrose , Regulação da Expressão Gênica , Idade Gestacional , Glomerulonefrite/genética , Glomerulonefrite/metabolismo , Glomerulonefrite/patologia , Glucocorticoides/metabolismo , Fator de Crescimento Insulin-Like I/genética , Fator de Crescimento Insulin-Like I/metabolismo , Glomérulos Renais/metabolismo , Glomérulos Renais/patologia , Masculino , Gravidez , Ratos Wistar , Receptor Tipo 2 de Angiotensina/genética , Receptor Tipo 2 de Angiotensina/metabolismo , Transdução de Sinais/genética
9.
Ecotoxicol Environ Saf ; 188: 109876, 2020 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-31704319

RESUMO

This study aimed to assess the levels of pyrethroids and organochlorine residues in the tissues of cultured Mugil capito and in water samples obtained from three different sites (Al-Hamol, Al-Riad and Sidi Salem; referred to as Area 1, Area 2, and Area 3, respectively) in the Delta region, Egypt. The study also assessed the biochemical markers in exposed mullet and evaluated the impact of these residues on the expression of insulin-like growth factor 1 (IGF-1) in muscle and cytochrome P4501A (CYP1A) in liver tissues using qRT-PCR and SDS-PAGE methods. The results revealed that pesticide residue levels in the water were variable, but were lower than detected levels in fish. Significant (P < 0.05) differences were found across the three study areas in terms of serum ALT, but the serum AST level was not significantly (P > 0.05) elevated in all study regions. Serum creatinine and urea levels were significantly (P < 0.05) elevated in area 3. Furthermore, glutathione and malondialdehyde concentrations significantly increased (P < 0.05) in liver tissues in area 3. Using the qRT-PCR technique, the results revealed that the expression level of IGF-1 was most significant in area 3, while the expression level of CYP1A was most significant in area 1. The protein profile showed some differences in band numbers and molecular weights of protein bands across different regions. Overall, the alteration in biochemical parameters revealed pesticide interference with the metabolic processes of fish. Furthermore, the pesticide pollution had an effect on the expression of IGF-1 and CYP1A genes and led to changes in the protein profile. Therefore, these markers can be used to monitor fish distress following exposure to the pollutant.


Assuntos
Família 1 do Citocromo P450/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Hidrocarbonetos Clorados/toxicidade , Fator de Crescimento Insulin-Like I/genética , Proteínas Musculares/metabolismo , Piretrinas/toxicidade , Smegmamorpha/metabolismo , Animais , Aquicultura , Egito , Biomarcadores Ambientais/genética , Hidrocarbonetos Clorados/análise , Hidrocarbonetos Clorados/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Proteínas Musculares/química , Resíduos de Praguicidas/análise , Resíduos de Praguicidas/metabolismo , Resíduos de Praguicidas/toxicidade , Piretrinas/análise , Piretrinas/metabolismo , Alimentos Marinhos/análise , Poluentes Químicos da Água/análise , Poluentes Químicos da Água/metabolismo
10.
Theriogenology ; 142: 433-440, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31711708

RESUMO

Heat stress hampers nutrient utilisation and production of animals, and dietary betaine supplementation can mitigate the adverse effects of heat stress on animals and improve their productivity. The present study was conducted to explore the effects of betaine supplementation on the growth performance of eighteen growing Karan Fries (KF) heifers having similar age and body conditions. The experiment was carried out on three groups (n = 6) of KF heifers viz. control, treatment I (betaine supplemented at 25  g/d/animal), and treatment II (betaine supplemented at 50  g/d/animal). The experiment lasted for eight months covering the three major seasons of Indian tropical conditions viz. hot-dry (temperature humidity index, THI = 83), hot-humid (THI = 85) and thermoneutral season (THI = 73). Blood samples were collected at fortnightly intervals and analysed for plasma growth hormone (GH; competitive ELISA) and total insulin-like growth factor 1 (IGF-1; Sandwich ELISA), as well as expression of IGF-I in peripheral blood mononuclear cells (PBMC) using real-time polymerase chain reaction. Betaine supplementation resulted in significant (p < 0.05) increase in dry matter intake, feed conversion efficiency, body weight gain, plasma GH and IGF-1 levels during all seasons. The concentrations of plasma IGF-1 and the mRNA expression of IGF-1 were higher (p < 0.01) in treatment I as compared to other groups during all seasons. Betaine supplementation at 25  g/d/animal was more cost-effective in improving growth performance of heat-stressed heifers as compared to 50  g/d/animal. The study suggests that the betaine protects intestinal integrity, enhances nutrient utilisation during heat stress and improves growth performance of growing heifers.


Assuntos
Betaína/administração & dosagem , Bovinos , Ingestão de Energia/efeitos dos fármacos , Transtornos de Estresse por Calor/dietoterapia , Resposta ao Choque Térmico/efeitos dos fármacos , Fator de Crescimento Insulin-Like I/genética , Ganho de Peso/efeitos dos fármacos , Fenômenos Fisiológicos da Nutrição Animal , Animais , Betaína/farmacologia , Bovinos/genética , Bovinos/crescimento & desenvolvimento , Suplementos Nutricionais , Ingestão de Energia/fisiologia , Feminino , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Crescimento e Desenvolvimento/efeitos dos fármacos , Crescimento e Desenvolvimento/genética , Transtornos de Estresse por Calor/sangue , Transtornos de Estresse por Calor/veterinária , Resposta ao Choque Térmico/fisiologia , Temperatura Alta , Umidade , Fator de Crescimento Insulin-Like I/metabolismo , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/metabolismo , Estações do Ano
11.
Gastroenterology ; 158(5): 1300-1312.e20, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31884074

RESUMO

BACKGROUND & AIMS: Human studies examining associations between circulating levels of insulin-like growth factor 1 (IGF1) and insulin-like growth factor binding protein 3 (IGFBP3) and colorectal cancer risk have reported inconsistent results. We conducted complementary serologic and Mendelian randomization (MR) analyses to determine whether alterations in circulating levels of IGF1 or IGFBP3 are associated with colorectal cancer development. METHODS: Serum levels of IGF1 were measured in blood samples collected from 397,380 participants from the UK Biobank, from 2006 through 2010. Incident cancer cases and cancer cases recorded first in death certificates were identified through linkage to national cancer and death registries. Complete follow-up was available through March 31, 2016. For the MR analyses, we identified genetic variants associated with circulating levels of IGF1 and IGFBP3. The association of these genetic variants with colorectal cancer was examined with 2-sample MR methods using genome-wide association study consortia data (52,865 cases with colorectal cancer and 46,287 individuals without [controls]) RESULTS: After a median follow-up period of 7.1 years, 2665 cases of colorectal cancer were recorded. In a multivariable-adjusted model, circulating level of IGF1 associated with colorectal cancer risk (hazard ratio per 1 standard deviation increment of IGF1, 1.11; 95% confidence interval [CI] 1.05-1.17). Similar associations were found by sex, follow-up time, and tumor subsite. In the MR analyses, a 1 standard deviation increment in IGF1 level, predicted based on genetic factors, was associated with a higher risk of colorectal cancer risk (odds ratio 1.08; 95% CI 1.03-1.12; P = 3.3 × 10-4). Level of IGFBP3, predicted based on genetic factors, was associated with colorectal cancer risk (odds ratio per 1 standard deviation increment, 1.12; 95% CI 1.06-1.18; P = 4.2 × 10-5). Colorectal cancer risk was associated with only 1 variant in the IGFBP3 gene region (rs11977526), which also associated with anthropometric traits and circulating level of IGF2. CONCLUSIONS: In an analysis of blood samples from almost 400,000 participants in the UK Biobank, we found an association between circulating level of IGF1 and colorectal cancer. Using genetic data from 52,865 cases with colorectal cancer and 46,287 controls, a higher level of IGF1, determined by genetic factors, was associated with colorectal cancer. Further studies are needed to determine how this signaling pathway might contribute to colorectal carcinogenesis.


Assuntos
Biomarcadores Tumorais/sangue , Neoplasias Colorretais/epidemiologia , Proteína 3 de Ligação a Fator de Crescimento Semelhante à Insulina/sangue , Fator de Crescimento Insulin-Like I/análise , Idoso , Biomarcadores Tumorais/genética , Estudos de Casos e Controles , Neoplasias Colorretais/sangue , Neoplasias Colorretais/genética , Feminino , Seguimentos , Humanos , Incidência , Proteína 3 de Ligação a Fator de Crescimento Semelhante à Insulina/genética , Fator de Crescimento Insulin-Like I/genética , Fator de Crescimento Insulin-Like II/análise , Masculino , Análise da Randomização Mendeliana , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Sistema de Registros/estatística & dados numéricos , Medição de Risco/métodos , Fatores de Risco , Fatores Sexuais , Reino Unido/epidemiologia
12.
J Biosci Bioeng ; 129(5): 632-637, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-31859190

RESUMO

Transplantation of stem cell-derived myoblasts is a promising approach for the treatment of skeletal muscle function loss. Myoblasts directly converted from somatic cells that bypass any stem cell intermediary stages can avoid the problem of tumor formation after transplantation. Previously, we reported that co-transduction with the myogenic differentiation 1 (MYOD1) gene and the v-myc avian myelocytomatosis viral oncogene lung carcinoma derived homolog (MYCL) gene efficiently converted human fibroblasts into myoblasts. Although the directly converted myoblasts efficiently fused into multinucleated myotubes in vitro and in vivo, it is not clear whether they have the contractile ability, which is the most significant phenotype of the muscle. In the present study, we aimed to examine the in vitro contractile ability of the myotubes differentiated from the directly converted myoblasts by the overexpression of MYOD1 and MYCL. We fabricated three-dimensional (3D) tissues on a microdevice for force measurement. The 3D culture enhanced the differentiation of the myoblasts into myotubes, which were confirmed by gene expression analysis of skeletal muscle-related genes. The tissues started to generate contractile force in response to electrical stimulation after 4 days of culture, which reached approximately 12 µN after 10 days. The addition of IGF-I decreased the contractile force of the 3D tissues, while the use of cryopreserved cells increased it. We confirmed that the tissues fabricated from the cells derived from three different donors generated forces of similar magnitude. Thus, directly converted myoblasts by the overexpression of MYOD1 and MYCL could be a promising cell source for cell therapy.


Assuntos
Fibroblastos/citologia , Músculo Esquelético/citologia , Mioblastos/citologia , Animais , Diferenciação Celular , Linhagem Celular , Fibroblastos/fisiologia , Humanos , Fator de Crescimento Insulin-Like I/genética , Fator de Crescimento Insulin-Like I/metabolismo , Contração Muscular , Desenvolvimento Muscular , Fibras Musculares Esqueléticas/citologia , Fibras Musculares Esqueléticas/fisiologia , Músculo Esquelético/fisiologia , Proteína MyoD/genética , Proteína MyoD/metabolismo , Mioblastos/fisiologia , Células-Tronco , Engenharia Tecidual
13.
Gen Comp Endocrinol ; 288: 113377, 2020 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-31881203

RESUMO

The synergy between the genetic potential and the nutrient intake determines the growth performance of meat-type chicken and nutrigenomics approach helps us understand the response of candidate genes of growth in chicken to dietary manipulations. The current study aimed to assess the growth performance and expression of hepatic growth related genes in the naked neck broiler chicken in response to different dietary energy and protein levels with a hypothesis that high plane of nutrition enhances both of these positively. The results revealed that birds have shown significantly better growth performance under high protein (HP) and high energy (HE) dietary regime. The expression profiles of the genes studied revealed upregulation of IGF-1, IGF-2, and GH under dietary HP and HE regime relative to other protein and energy levels with greater upregulation at 3rd week than the 1st and 5th week of age of birds. The IGFR and GHR mRNA expression was significantly higher under HP and HE dietary regimen with an increasing and decreasing trend from 1st to 5th week of age, respectively. A consistent and significant downregulation of IGFBP-2 was observed under HP and HE regime throughout the feeding trial. The myostatin expression was higher at 3rd week of age followed by 1st week expression. The HP and HE as well as LP (Low protein) and HE diet resulted in significant upregulation of myostatin gene expression in liver. In support to the set hypothesis of this study the high protein and high energy diet resulted in better growth performance of broiler chickens with corresponding upregulation of IGF-1, IGF-2, IGFR, GH, GHR, and Myostatin gene expression and downregulation of IGFBP-2 in liver.


Assuntos
Galinhas/crescimento & desenvolvimento , Galinhas/genética , Dieta , Proteínas na Dieta/administração & dosagem , Metabolismo Energético/efeitos dos fármacos , Ração Animal , Fenômenos Fisiológicos da Nutrição Animal/genética , Animais , Galinhas/metabolismo , Proteínas na Dieta/farmacologia , Ingestão de Energia/efeitos dos fármacos , Metabolismo Energético/genética , Feminino , Expressão Gênica/efeitos dos fármacos , Hormônio do Crescimento/genética , Hormônio do Crescimento/metabolismo , Proteína 2 de Ligação a Fator de Crescimento Semelhante à Insulina/genética , Proteína 2 de Ligação a Fator de Crescimento Semelhante à Insulina/metabolismo , Fator de Crescimento Insulin-Like I/genética , Fator de Crescimento Insulin-Like I/metabolismo , Fator de Crescimento Insulin-Like II/genética , Fator de Crescimento Insulin-Like II/metabolismo , Masculino , Distribuição Aleatória , Receptor IGF Tipo 1/genética , Receptor IGF Tipo 1/metabolismo
14.
Anim Reprod Sci ; 211: 106206, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31785637

RESUMO

This study was conducted to evaluate associations of polymorphisms in the genes for the growth hormone receptor (GHR), insulin-like growth factor I (IGF-I) and signal transducer and activator of transcription 5A (STAT5A) with serum concentrations of IGF-I, reproductive performance and milk production of postpartum Holstein dairy cows. Days from calving to first ovulation (DTO) and calving to conception interval (CCI) were evaluated in 95 Holstein cows. Serum concentrations of IGF-I and ß-hydroxybutyrate (BHBA) were quantified in samples collected in sequential blood collections. Genotyping of the IGF-I and STAT5A genes was performed. The IGF-I polymorphism distribution was 35.9% CC, 46.1% CT and 18% TT. The IGF-I concentrations in circulation were greater in cows of the TT compared with both the CT and CC groups (P < 0.05). Genotype had a linear association (P < 0.05) with DTO and CCI, which were less for cows of the TT group. There was no association of STAT5A BstEII on serum IGF-I or reproductive variables (P> 0.05). When combining the GHR AluI T allele, obtained in a previous study, and the IGF-I SnaBI T allele from the current study, for the same cows, there were additive associations of both with serum IGF-I, BHBA, number of services per conception, DTO and CCI (P < 0.05). Thus, the IGF-1 SnaBI TT appears to be associated with fewer DTO and lesser CCI of lactating dairy cows and had an additive association with the GHR AluI T allele on indicators for improvement of fertility.


Assuntos
Bovinos/fisiologia , Fator de Crescimento Insulin-Like I/genética , Fator de Crescimento Insulin-Like I/metabolismo , Polimorfismo de Nucleotídeo Único , Receptores da Somatotropina/genética , Fator de Transcrição STAT5/genética , Animais , Bovinos/genética , Feminino
15.
J Biomed Sci ; 26(1): 94, 2019 Dec 02.
Artigo em Inglês | MEDLINE | ID: mdl-31787098

RESUMO

BACKGROUND: Insulin-like growth factor 1 (IGF-1) is an important pleiotropic hormone that exerts neuroprotective and neuroreparative effects after a brain injury. However, the roles of IGF-1 variants in mild traumatic brain injury (mTBI) are not yet fully understood. This study attempted to elucidate the effects of IGF-1 variants on the risk and neuropsychiatric outcomes of mTBI. METHODS: Based on 176 recruited mTBI patients and 1517 control subjects from the Taiwan Biobank project, we first compared the genotypic distributions of IGF-1 variants between the two groups. Then, we analyzed associations of IGF-1 variants with neuropsychiatric symptoms after mTBI, including anxiety, depression, dizziness, and sleep disturbances. Functional annotation of IGF-1 variants was also performed through bioinformatics databases. RESULTS: The minor allele of rs7136446 was over-represented in mTBI patients compared to community-based control subjects. Patients carrying minor alleles of rs7136446 and rs972936 showed more dizziness and multiple neuropsychiatric symptoms after brain injury. CONCLUSIONS: IGF-1 variants were associated with the risk and neuropsychiatric symptoms of mTBI. The findings highlight the important role of IGF-1 in the susceptibility and clinical outcomes of mTBI.


Assuntos
Ansiedade/genética , Concussão Encefálica/genética , Depressão/genética , Tontura/genética , Fator de Crescimento Insulin-Like I/genética , Polimorfismo Genético , Transtornos do Sono-Vigília/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Ansiedade/etiologia , Concussão Encefálica/complicações , Depressão/etiologia , Tontura/etiologia , Feminino , Humanos , Fator de Crescimento Insulin-Like I/metabolismo , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Transtornos do Sono-Vigília/etiologia , Taiwan , Adulto Jovem
16.
Medicine (Baltimore) ; 98(46): e18017, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31725675

RESUMO

BACKGROUND: Several studies have been conducted on the relationship between insulin-like growth factor 1 gene (IGF-1) rs35767 polymorphisms and cancer risk, but the results are conflicting. We performed a meta-analysis to investigate the relationship between IGF-1 rs35767 polymorphisms and cancer risk. METHODS: Eight studies (5 for IGF-1 rs35767 C>T and 3 for IGF-1 rs35767 A>G) with a total of 11,257 cases and 16,213 controls were included. The studies were about the association between IGF-1 rs35767 polymorphisms and cancer risk and acquired by searching PubMed, Embase, and Web of Science databases for articles published before January 20, 2019. STATA software was used to analyze the data and identify the strength of the association by using pooled-odds ratios (ORs) with corresponding 95% confidence intervals (CIs). RESULTS: No significant associations were observed between the IGF-1 rs35767 C>T polymorphism and cancer risk in all genetic models. However, the IGF-1 rs35767 A>G polymorphism was significantly associated with increased cancer risk for all genetic models (G vs A: OR = 1.087, 95% CI: 1.036-1.141, Ph = .338; GG vs AA: OR = 1.272, 95% CI: 1.121-1.442, Ph = .359; AG vs AA: OR = 1.187, 95% CI: 1.043-1.351, Ph = .695; AG+GG vs AA: OR = 1.187, 95% CI: 1.043-1.351, Ph = .695; GG vs AA+AG: OR = 1.086, 95% CI: 1.025-1.151, Ph = .275). Begg and Egger tests showed that no publication bias existed. CONCLUSION: Our findings indicated that the IGF-1 rs35767 A>G polymorphism might be a risk factor for cancer development. However, additional well-designed studies with sample sizes larger than ours need to be conducted in the future to verify our findings.


Assuntos
Fator de Crescimento Insulin-Like I/genética , Neoplasias/genética , Alelos , Predisposição Genética para Doença , Humanos , Razão de Chances , Polimorfismo de Nucleotídeo Único , Fatores de Risco
17.
Cell Physiol Biochem ; 53(5): 851-864, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31714043

RESUMO

BACKGROUND/AIMS: The growth promoting effect of lysine and betaine as well as the expression of candidate genes reflecting their efficacy, such as ghrelin, leptin, Growth Hormone Secretagogue Receptor (GHS-R), Insulin like Growth Factor (IGF- 1) and Growth Hormone Releasing Hormone (GHRH) was examined in Labeo rohita fingerlings. METHODS: One hundred eighty healthy juveniles from a homologous population were randomly distributed to 15 rectangular tanks of 150 litres capacity. The experiment was carried out for 60 days with five treatment groups consisting T1 (0.25% Betaine), T2 (0.5% Betaine), T3 (0.75% Lysine) and T4 (1.5% Lysine) and control group. The experiment was carried out for 60 days with five treatment groups consisting T1 (0.25% Betaine), T2 (0.5% Betaine), T3 (0.75% Lysine) and T4 (1.5% Lysine) and control group. At the end of trial, the growth parameters such as weight gain, SGR, PER were estimated from the weight of the triplicate groups. The digestive, metabolic and antioxidant enzymes were analysed using spectrophotometric methods. The intestine, brain and liver were sampled from the treatments and expression of different genes ghrelin, leptin, GHSR, IGF-1 and GHRH was also performed by realtime PCR. RESULTS: A significant (P<0.05) increase in weight gain, SGR, PER and lowest FCR was found in T4 group which was significantly (p < 0.05) different from other experimental groups. The highest mRNA expression levels of expression were found in T4 group which was similar to that of ghrelin gene mRNA of T2 group. The significantly (p<0.05) highest GHSR, GHRH and IGF-1 gene expression levels were found in T4 treatment group compared to other groups. CONCLUSION: The present study reveals that the lysine and betaine stimulate growth and expression of ghrelin GHRH, GHS-R and IGF-1 genes. The increase of IGF-I mRNA expression with lysine and betaine supplementation revealed that these compounds act as growth modulators. However, lysine was found to be a more potent modulator of growth compared to betaine.


Assuntos
Betaína/farmacologia , Cyprinidae/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Lisina/farmacologia , Ração Animal , Animais , Catalase/metabolismo , Cyprinidae/crescimento & desenvolvimento , Grelina/genética , Grelina/metabolismo , Hormônio Liberador de Hormônio do Crescimento/genética , Hormônio Liberador de Hormônio do Crescimento/metabolismo , Fator de Crescimento Insulin-Like I/genética , Fator de Crescimento Insulin-Like I/metabolismo , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/metabolismo , Leptina/genética , Leptina/metabolismo , Fígado/enzimologia , Fígado/metabolismo , Receptores de Grelina/genética , Receptores de Grelina/metabolismo , Superóxido Dismutase/metabolismo
18.
Ginekol Pol ; 90(10): 596-603, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31686417

RESUMO

OBJECTIVES: Pre-eclampsia (PE) affects many women worldwide and remains the leading cause of morbidity and mortality in neonatal and maternal settings. Abnormal expression of placental microRNAs (miRNAs) may be associated with PE. MATERIAL AND METHODS: This study was conducted to the relationship between IGF1 and the expression spectrum of miRNA in the placenta of preeclampsia patient. The expression of miRNA in placental tissue was compared between pre-eclampsia (n = 6) and normal pregnant women (n = 5) miRNA targets were studied by computer simulation and functional assays. The role of miRNA was verified in trophoblast cell lines by apoptosis assay and invasion assay. RESULTS: There was a significant increase in miRNAs in the placenta of women with pre-eclampsia compared with patients with normal pregnancy. Luciferase assay confirmed direct regulation of miRNA. CONCLUSIONS: The expression of IGF1 and miRNA was significantly increased in the placenta of patients with pre-eclampsia.


Assuntos
Fator de Crescimento Insulin-Like I/genética , MicroRNAs/genética , Placenta/metabolismo , Pré-Eclâmpsia/genética , Análise por Conglomerados , Feminino , Humanos , Fator de Crescimento Insulin-Like I/metabolismo , MicroRNAs/metabolismo , Placenta/química , Pré-Eclâmpsia/epidemiologia , Pré-Eclâmpsia/metabolismo , Gravidez , Transdução de Sinais/genética
19.
Drug Des Devel Ther ; 13: 3161-3170, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31564832

RESUMO

Purpose: To investigate the role of IGF-1 signaling pathway in the treatment of uterine leiomyomas with mifepristone. Patients and methods: From October 2015 to December 2018, 50 patients with uterine leiomyoma were included in this study. Overexpression or siRNA of IGF-1 in primary human uterine leiomyoma cells were treated with or without mifepristone. MTT was used to evaluate cell viability in assays of cell proliferation and cytotoxicity. IGF-1 expression in the cells was measured with real-time RT-PCR and Western blotting and manipulated with lentivirus ectopic overexpression or siRNA silencing. Results: Inhibition of cell viability by mifepristone was found dependent on drug concentration and treatment time. IGF-1 and phosphorylation-ERK1/2 expression were decreased, while phosphorylation-AKT expression was increased after mifepristone treatment. IGF-1 significantly promoted cell growth, while IGF-1 knockdown and mifepristone showed synergistic inhibition effects on cell growth. The overexpression of IGF-1 reversed the inhibition of cell growth and ERK1/2 phosphorylation but showed no effect on AKT phosphorylation. Conclusion: Our study for the first time demonstrated that IGF-1 signaling via ERK1/2 appears to be an important target of mifepristone in the treatment of uterine leiomyomas, which may provide a new approach to avoid leiomyoma re-growth after cessation of mifepristone.


Assuntos
Antineoplásicos/farmacologia , Fator de Crescimento Insulin-Like I/antagonistas & inibidores , Leiomioma/tratamento farmacológico , Mifepristona/farmacologia , Transdução de Sinais/efeitos dos fármacos , Neoplasias Uterinas/tratamento farmacológico , Adulto , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Fator de Crescimento Insulin-Like I/genética , Fator de Crescimento Insulin-Like I/metabolismo , Leiomioma/metabolismo , Leiomioma/patologia , Células Tumorais Cultivadas , Neoplasias Uterinas/metabolismo , Neoplasias Uterinas/patologia
20.
PLoS Biol ; 17(10): e3000509, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31613895

RESUMO

The Hippo signalling pathway restricts cell proliferation in animal tissues by inhibiting Yes-associated protein (YAP or YAP1) and Transcriptional Activator with a PDZ domain (TAZ or WW-domain-containing transcriptional activator [WWTR1]), coactivators of the Scalloped (Sd or TEAD) DNA-binding transcription factor. Drosophila has a single YAP/TAZ homolog named Yorkie (Yki) that is regulated by Hippo pathway signalling in response to epithelial polarity and tissue mechanics during development. Here, we show that Yki translocates to the nucleus to drive Sd-mediated cell proliferation in the ovarian follicle cell epithelium in response to mechanical stretching caused by the growth of the germline. Importantly, mechanically induced Yki nuclear localisation also requires nutritionally induced insulin/insulin-like growth factor 1 (IGF-1) signalling (IIS) via phosphatidyl inositol-3-kinase (PI3K), phosphoinositide-dependent kinase 1 (PDK1 or PDPK1), and protein kinase B (Akt or PKB) in the follicular epithelium. We find similar results in the developing Drosophila wing, where Yki becomes nuclear in the mechanically stretched cells of the wing pouch during larval feeding, which induces IIS, but translocates to the cytoplasm upon cessation of feeding in the third instar stage. Inactivating Akt prevents nuclear Yki localisation in the wing disc, while ectopic activation of the insulin receptor, PI3K, or Akt/PKB is sufficient to maintain nuclear Yki in mechanically stimulated cells of the wing pouch even after feeding ceases. Finally, IIS also promotes YAP nuclear localisation in response to mechanical cues in mammalian skin epithelia. Thus, the Hippo pathway has a physiological function as an integrator of epithelial cell polarity, tissue mechanics, and nutritional cues to control cell proliferation and tissue growth in both Drosophila and mammals.


Assuntos
Proteínas de Drosophila/genética , Drosophila melanogaster/genética , Células Epiteliais/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/genética , Proteínas Nucleares/genética , Fosfatidilinositol 3-Quinase/genética , Proteínas Serina-Treonina Quinases/genética , Proteínas Proto-Oncogênicas c-akt/genética , Transativadores/genética , Proteínas Quinases Dependentes de 3-Fosfoinositídeo/genética , Proteínas Quinases Dependentes de 3-Fosfoinositídeo/metabolismo , Animais , Fenômenos Biomecânicos , Núcleo Celular/metabolismo , Núcleo Celular/ultraestrutura , Polaridade Celular , Proliferação de Células , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/citologia , Drosophila melanogaster/crescimento & desenvolvimento , Drosophila melanogaster/metabolismo , Células Epiteliais/citologia , Feminino , Regulação da Expressão Gênica no Desenvolvimento , Humanos , Fator de Crescimento Insulin-Like I/genética , Fator de Crescimento Insulin-Like I/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Larva/citologia , Larva/genética , Larva/crescimento & desenvolvimento , Larva/metabolismo , Mecanotransdução Celular , Camundongos , Proteínas Nucleares/metabolismo , Folículo Ovariano/citologia , Folículo Ovariano/crescimento & desenvolvimento , Folículo Ovariano/metabolismo , Fosfatidilinositol 3-Quinase/metabolismo , Transporte Proteico , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptor de Insulina/genética , Receptor de Insulina/metabolismo , Transativadores/metabolismo , Asas de Animais/citologia , Asas de Animais/crescimento & desenvolvimento , Asas de Animais/metabolismo
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