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1.
J Pharmacol Sci ; 144(3): 119-122, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32921392

RESUMO

Multiple sclerosis (MS) is a demyelinating disease of the central nervous system, characterized by apoptotic death of mature oligodendrocytes, neuroinflammation, and motor dysfunction. A pentacyclic triterpenoid compound, ursolic acid (UA), has various pharmacological activities, such as anti-inflammatory, anti-oxidative, and anti-apoptotic effects. In the present study, we investigated the effects of UA on cuprizone-induced demyelination, which is a model of MS. Oral administration of UA effectively suppressed cuprizone-induced demyelination and motor dysfunction via the enhancement of IGF-1 levels in the demyelinating lesions. Our results suggest that UA might be therapeutically useful for demyelination in MS.


Assuntos
Cuprizona/efeitos adversos , Doenças Desmielinizantes/tratamento farmacológico , Doenças Desmielinizantes/genética , Expressão Gênica/efeitos dos fármacos , Fator de Crescimento Insulin-Like I/genética , Fator de Crescimento Insulin-Like I/metabolismo , Atividade Motora/efeitos dos fármacos , Atividade Motora/genética , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla/genética , Triterpenos/administração & dosagem , Triterpenos/farmacologia , Regulação para Cima/efeitos dos fármacos , Administração Oral , Animais , Doenças Desmielinizantes/induzido quimicamente , Doenças Desmielinizantes/fisiopatologia , Modelos Animais de Doenças , Camundongos , Esclerose Múltipla/induzido quimicamente , Esclerose Múltipla/fisiopatologia
2.
PLoS One ; 15(9): e0238393, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32877466

RESUMO

Insulin-like growth factors 2 and 1 (IGF2 and IGF1) and insulin are closely related hormones that are responsible for the regulation of metabolic homeostasis, development and growth of the organism. Physiological functions of insulin and IGF1 are relatively well-studied, but information about the role of IGF2 in the body is still sparse. Recent discoveries called attention to emerging functions of IGF2 in the brain, where it could be involved in processes of learning and memory consolidation. It was also proposed that these functions could be mediated by the receptor for IGF2 (IGF2R). Nevertheless, little is known about the mechanism of signal transduction through this receptor. Here we produced His-tagged domain 11 (D11), an IGF2-binding element of IGF2R; we immobilized it on the solid support through a well-defined sandwich, consisting of neutravidin, biotin and synthetic anti-His-tag antibodies. Next, we prepared specifically radiolabeled [125I]-monoiodotyrosyl-Tyr2-IGF2 and optimized a sensitive and robust competitive radioligand binding assay for determination of the nanomolar binding affinities of hormones for D11 of IGF2. The assay will be helpful for the characterization of new IGF2 mutants to study the functions of IGF2R and the development of new compounds for the treatment of neurological disorders.


Assuntos
Fator de Crescimento Insulin-Like II/metabolismo , Receptor IGF Tipo 2/imunologia , Receptor IGF Tipo 2/ultraestrutura , Ligação Competitiva , Células Cultivadas , Humanos , Fator de Crescimento Insulin-Like I/metabolismo , Radioisótopos do Iodo , Ligação Proteica , Ensaio Radioligante/métodos , Transdução de Sinais
3.
Gene ; 760: 145018, 2020 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-32758580

RESUMO

Protein turnover is a process that is regulated by several factors and can lead to muscle hypertrophy or atrophy. The purpose of the present study was to determine the effects of ß-hydroxy-ß-methylbutyrate free acid (HMB-FA) and eccentric resistance exercise on variables related to protein turnover in rats. Thirty-two male rats were randomly assigned into four groups of eight, including control, control-HMB, exercise, and exercise-HMB. Animals in HMB groups received 340 mg/kg/day for two weeks. Animals in the exercise groups performed one session of eccentric resistance exercise consisting of eight repetitions descending from a ladder with a slope of 80 degree, with an extra load of two times body weight (100% 1RM). Twenty-four hours after the exercise session, triceps brachii muscle and serum were collected for further analysis. Exercise and HMB-FA induced lower muscle myostatin and higher muscle Fibronectin type III domain containing 5 (FNDC5), P70-S6 kinase 1 gene expression, as well as higher serum irisin and IGF-1 concentrations. Exercise alone induced higher caspase-3 and caspase-8 gene expression while HMB-FA alone induced lower caspase 3 gene expression. HMB-FA supplement increased the effect of exercise on muscle FNDC5, myostatin, and P70-S6 kinase 1 gene expression. The interaction of exercise and HMBFA resulted in an additive effect, increasing serum irisin and IGF-1 concentrations. In conclusion, a 2-week HMB-FA supplementation paired with acute eccentric resistance exercise can positively affect some genes related to muscle protein turnover.


Assuntos
Proteínas Musculares/efeitos dos fármacos , Valeratos/farmacologia , Animais , Suplementos Nutricionais , Fibronectinas/efeitos dos fármacos , Fibronectinas/metabolismo , Genes Reguladores/genética , Fator de Crescimento Insulin-Like I/metabolismo , Masculino , Proteínas Musculares/metabolismo , Músculo Esquelético/metabolismo , Miostatina/efeitos dos fármacos , Miostatina/metabolismo , Condicionamento Físico Animal/métodos , Ratos , Ratos Sprague-Dawley , Treinamento de Resistência/métodos , Proteínas Quinases S6 Ribossômicas 70-kDa/efeitos dos fármacos , Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo
4.
J Cancer Res Clin Oncol ; 146(11): 2861-2870, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32772171

RESUMO

PURPOSE: IGF-1Ec is an isoform of Insulin-like growth factor 1 (IGF-1) and has recently been identified to be overexpressed in cancers including prostate and neuroendocrine tumours. The aim of this paper is to investigate the expression of IGF-1Ec in colorectal cancer and polyps compared to normal colon tissues and its association with recurrent disease using semi-quantitative immunohistochemistry. METHODS: Immunohistochemistry for IGF-1Ec expression was performed for colorectal cancer, colorectal polyps and normal colonic tissues. The quantification of IGF-1Ec expression was performed with the use of Image J software and the IHC profiler plugin. Following ethics approval from the National Research Ethics Service (Reference 11/LO/1521), clinical information including recurrent disease on follow-up was collected for patients with colorectal cancer. RESULTS: Immunohistochemistry was performed in 16 patients with colorectal cancer and 11 patients with colonic polyps and compared to normal colon tissues and prostate adenocarcinoma (positive control) tissues. Significantly increased expression of IGF-1Ec was demonstrated in colorectal cancer (p < 0.001) and colorectal polyps (p < 0.05) compared to normal colonic tissues. Colonic adenomas with high-grade dysplasia had significantly higher expression of IGF-1Ec compared to low-grade dysplastic adenomas (p < 0.001). Colorectal cancers without lymph node metastases at the time of presentation had significantly higher IGF-1Ec expression compared to lymph node-positive disease (p < 0.05). No correlation with recurrent disease was identified with IGF-1Ec expression. CONCLUSION: IGF-1Ec is significantly overexpressed in colorectal cancer and polyps compared to normal colon tissues offering a potential target to improve colonoscopic identification of colorectal polyps and cancer and intraoperative identification of colorectal tumours.


Assuntos
Pólipos Adenomatosos/diagnóstico , Pólipos do Colo/diagnóstico , Neoplasias Colorretais/diagnóstico , Fator de Crescimento Insulin-Like I/metabolismo , Pólipos Adenomatosos/metabolismo , Pólipos Adenomatosos/patologia , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/análise , Pólipos do Colo/metabolismo , Pólipos do Colo/patologia , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Feminino , Humanos , Imuno-Histoquímica/métodos , Fator de Crescimento Insulin-Like I/análise , Masculino
5.
Chem Biol Interact ; 328: 109144, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32653415

RESUMO

The debilitating nature of cognitive impairment in epilepsy and the potential of some traditional antiepileptics to further deteriorate cognitive function are areas of growing concern. Glucagon-like peptide-1 (GLP-1) deficiency has been linked to reduced seizure threshold as well as cognitive dysfunction. Here, we tested whether sitagliptin (SITA), by virtue of its neuroprotective properties, could alleviate both epilepsy and associated cognitive dysfunction in a rat model of kindling epilepsy. Chemical kindling was induced by subconvulsive doses of pentylenetetrazol (PTZ) (30 mg/kg; i.p). SITA (50 mg/kg; p.o) was administered 1 h before PTZ injections. SITA conceivably attenuated PTZ hippocampal histological insult, preserved neuronal integrity and amended neurotransmitter perturbations in rat hippocampi paralleled with enhanced hippocampal GLP-1 levels as well as the downstream cAMP content and protein kinase A (PKA) activity. Moreover, SITA improved cognitive functioning of rats in the Morris water maze which was coupled with hampered hippocampal p(Ser404)-tau and ß-amyloid proteins. SITA replenished p(Ser9)-glycogen synthase kinase-3ß (GSK-3ß). It also opposed the boosted matrix metalloproteinase-9 (MMP-9), brain-derived neurotrophic factor (BDNF), and insulin-like growth factor-1 (IGF-1) levels associated with PTZ administration along with mitigation of both ß-secretase-1 (BACE1) immunoreactivity and receptor for advanced glycation end products (RAGE) protein level in rat hippocampi. In conclusion, SITA subdues epileptic and cognitive upshots of PTZ kindling in rats, which might correspond to the modulation of BACE1, amyloidogenic/RAGE axis as well as GSK-3ß/MMP-9/BDNF signaling cascade. SITA effects are probably mediated via boosting GLP-1 and subsequently enhancing GLP-1/GLP-1R signaling.


Assuntos
Secretases da Proteína Precursora do Amiloide/metabolismo , Amiloide/metabolismo , Ácido Aspártico Endopeptidases/metabolismo , Transtornos Cognitivos/induzido quimicamente , Transtornos Cognitivos/metabolismo , Excitação Neurológica/efeitos dos fármacos , Receptor para Produtos Finais de Glicação Avançada/metabolismo , Transdução de Sinais , Fosfato de Sitagliptina/farmacologia , Peptídeos beta-Amiloides/metabolismo , Animais , Biomarcadores/metabolismo , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Transtornos Cognitivos/patologia , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Glicogênio Sintase Quinase 3 beta/metabolismo , Hipocampo/efeitos dos fármacos , Hipocampo/patologia , Fator de Crescimento Insulin-Like I/metabolismo , Masculino , Metaloproteinase 9 da Matriz/metabolismo , Inibição Neural/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/patologia , Neurotransmissores/metabolismo , Pentilenotetrazol , Ratos Wistar , Convulsões/induzido quimicamente , Convulsões/metabolismo , Convulsões/patologia , Transdução de Sinais/efeitos dos fármacos , Memória Espacial/efeitos dos fármacos , Proteínas tau/metabolismo
6.
Nature ; 583(7817): 620-624, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32669709

RESUMO

Approximately 75% of all breast cancers express the oestrogen and/or progesterone receptors. Endocrine therapy is usually effective in these hormone-receptor-positive tumours, but primary and acquired resistance limits its long-term benefit1,2. Here we show that in mouse models of hormone-receptor-positive breast cancer, periodic fasting or a fasting-mimicking diet3-5 enhances the activity of the endocrine therapeutics tamoxifen and fulvestrant by lowering circulating IGF1, insulin and leptin and by inhibiting AKT-mTOR signalling via upregulation of EGR1 and PTEN. When fulvestrant is combined with palbociclib (a cyclin-dependent kinase 4/6 inhibitor), adding periodic cycles of a fasting-mimicking diet promotes long-lasting tumour regression and reverts acquired resistance to drug treatment. Moreover, both fasting and a fasting-mimicking diet prevent tamoxifen-induced endometrial hyperplasia. In patients with hormone-receptor-positive breast cancer receiving oestrogen therapy, cycles of a fasting-mimicking diet cause metabolic changes analogous to those observed in mice, including reduced levels of insulin, leptin and IGF1, with the last two remaining low for extended periods. In mice, these long-lasting effects are associated with long-term anti-cancer activity. These results support further clinical studies of a fasting-mimicking diet as an adjuvant to oestrogen therapy in hormone-receptor-positive breast cancer.


Assuntos
Neoplasias da Mama/dietoterapia , Neoplasias da Mama/tratamento farmacológico , Dietoterapia/métodos , Jejum/fisiologia , Fulvestranto/uso terapêutico , Animais , Fatores Biológicos/sangue , Neoplasias da Mama/patologia , Dieta Saudável/métodos , Modelos Animais de Doenças , Progressão da Doença , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Proteína 1 de Resposta de Crescimento Precoce/metabolismo , Feminino , Fulvestranto/administração & dosagem , Humanos , Insulina/sangue , Fator de Crescimento Insulin-Like I/metabolismo , Leptina/sangue , Células MCF-7 , Camundongos Endogâmicos NOD , Camundongos SCID , PTEN Fosfo-Hidrolase/metabolismo , Piperazinas/administração & dosagem , Piperazinas/uso terapêutico , Piridinas/administração & dosagem , Piridinas/uso terapêutico , Receptores Estrogênicos , Receptores de Progesterona , Tamoxifeno/efeitos adversos , Tamoxifeno/uso terapêutico , Ensaios Antitumorais Modelo de Xenoenxerto
7.
Anim Sci J ; 91(1): e13402, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32512645

RESUMO

This study aimed to evaluate the effects of supplementing Saccharomyces cerevisiae (SC) during the pre- and post-weaning periods on growth, metabolic and hormonal responses, and rumen fermentation in calves. Three-week-old Holstein calves were assigned to either control (n = 12) or SC group (n = 12), the latter of which received 2 × 109  cfu/day of SC. The experiment was conducted over a period of 7 weeks around weaning. Daily gain (DG) in the SC group was higher (p < .05) than that in the control group. In the SC group, plasma glucose, insulin, and growth hormone (GH) concentrations were higher (p < .05) and concentrations of glucagon and insulin-like growth factor 1 (IGF-1) tended to be higher (p < .1) than in the control group. Proportion of rumen propionate and concentration of rumen ammonia nitrogen at 10 weeks of age were greater (p < .05) in the SC group than that in the control group. Supplementation of SC around weaning may improve dietary nutrient and energy availability and increase plasma GH and IGF-1 concentrations. These changes observed in SC-supplemented calves could be closely related to the improvement of DG.


Assuntos
Ração Animal , Fenômenos Fisiológicos da Nutrição Animal , Bovinos/crescimento & desenvolvimento , Bovinos/metabolismo , Dieta/veterinária , Suplementos Nutricionais , Fermentação , Hormônio do Crescimento/metabolismo , Fator de Crescimento Insulin-Like I/metabolismo , Rúmen/metabolismo , Saccharomyces cerevisiae , Animais , Glicemia/metabolismo , Feminino , Glucagon , Insulina/metabolismo , Masculino , Desmame
8.
Adv Cancer Res ; 147: 229-257, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32593402

RESUMO

The insulin and insulin-like growth factor (IGF) family of proteins are part of a complex network that regulates cell proliferation and survival. While this system is undoubtedly important in prenatal development and postnatal cell growth, members of this family have been implicated in several different cancer types. Increased circulating insulin and IGF ligands have been linked to increased risk of cancer incidence. This observation has led to targeting the IGF system as a therapeutic strategy in a number of cancers. This chapter aims to describe the well-characterized biology of the IGF1R system, outline the rationale for targeting this system in cancer, summarize the clinical data as it stands, and discuss where we can go from here.


Assuntos
Fator de Crescimento Insulin-Like I/antagonistas & inibidores , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Receptor IGF Tipo 1/antagonistas & inibidores , Animais , Humanos , Fator de Crescimento Insulin-Like I/metabolismo , Terapia de Alvo Molecular , Neoplasias/patologia , Receptor IGF Tipo 1/metabolismo , Transdução de Sinais
9.
Toxicol Lett ; 331: 167-177, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32535229

RESUMO

Prenatal ethanol exposure (PEE) could increase offspring's susceptibility to adult liver lipid-metabolism diseases. This study aimed to confirm intrauterine programming mechanism of glucocorticoid-insulin-like growth factor 1 (GC-IGF1) axis for liver dysfunction in offspring rats induced by PEE. The results showed that levels of hepatic IGF1, lipid metabolism-related enzymes (e.g. FASN and HMGCR) and serum phenotype (TG, TCH, HDL-C, and LDL-C) were low in fetal rats of PEE but high in adult offspring except for HDL-C, meanwhile, hepatic H3K9ac and expression levels of IGF1 were low in fetal rats but high in adult offspring. Furthermore, levels of serum corticosterone and hepatic glucocorticoid-activation system (mainly including expression of 11ß-HSD1, GR, and C/EBPα as well as 11ß-HSD1/11ß-HSD2 ratio) were high in fetal rats of PEE but low or unchanged in adult offspring. The adult F2 generation of PEE maintained the same GC-IGF1 axis programming alteration as the F1 generation despite gender differences. In vitro, cortisol was proved to activate hepatocyte glucocorticoid-activation system and decrease H3K9ac and expression levels of IGF1 by GR. Therefore, PEE has a long-term effect on the offspring's liver functional development, which may be mainly related to the epigenetic programming alteration of the GC-IGF1 axis mediated by the glucocorticoid-activation system.


Assuntos
Etanol/toxicidade , Glucocorticoides/metabolismo , Fator de Crescimento Insulin-Like I/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Animais , Peso Corporal , Corticosterona/sangue , Feminino , Retardo do Crescimento Fetal/sangue , Retardo do Crescimento Fetal/induzido quimicamente , Retardo do Crescimento Fetal/metabolismo , Células Hep G2 , Humanos , Lipídeos/sangue , Fígado/embriologia , Fígado/metabolismo , Masculino , Gravidez , Efeitos Tardios da Exposição Pré-Natal/sangue , Ratos Wistar , Transdução de Sinais
10.
Anim Sci J ; 91(1): e13390, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32468653

RESUMO

This study was carried out to evaluate the nutritional effects of rice feeding and carnitine addition to a diet for broiler chicks. Thirty-six male 10-day-old broiler chicks were assigned to one of the following four treatment groups: corn-based diet (corn group), rice-based diet (rice group), and each diet with added carnitine (100 ppm). The experimental period was 2 weeks. Rice feeding resulted in significantly higher growth performance (body weight gain and feed efficiency) compared to corn feeding. Carnitine addition also resulted in higher growth performance. Breast muscle and thigh muscle weight (g) were significantly higher in broiler chicks fed rice and those fed diets with added carnitine. Liver mRNA expression of IGF-I was significantly higher in broiler chicks fed rice compared to those fed corn. There was no significant difference in mRNA expression of muscle atrogin-1 or liver CPT-I between broiler chicks fed rice and those fed corn, not between broilers chicks fed diets containing carnitine or not. Overall, these results show that rice feeding and carnitine addition improve the growth performance of broiler chicks by increasing mRNA expression of liver IGF-I. In addition, carnitine action is not affected by different cereals (corn and rice).


Assuntos
Ração Animal , Fenômenos Fisiológicos da Nutrição Animal/genética , Fenômenos Fisiológicos da Nutrição Animal/fisiologia , Carnitina/administração & dosagem , Galinhas/crescimento & desenvolvimento , Galinhas/genética , Galinhas/metabolismo , Dieta/veterinária , Suplementos Nutricionais , Expressão Gênica , Fator de Crescimento Insulin-Like I/genética , Fator de Crescimento Insulin-Like I/metabolismo , Oryza , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Animais , Fígado/metabolismo , Masculino , Zea mays
11.
Am J Chin Med ; 48(4): 1005-1019, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32468825

RESUMO

Harboring insulin-producing cells, the pancreas has more interstitial insulin than any other organ. In vitro, insulin activates both insulin receptor (IR) and insulin-like growth factor-1 receptor (IGF1R) to stimulate pancreatic cancer cells. Whether intra-pancreatic insulin nourishes pancreatic cancer cells in vivo remains uncertain. In the present studies, we transplanted human pancreatic cancer cells orthotopically in euglycemic athymic mice whose intra-pancreatic insulin was intact or was decreased following pretreatment with streptozotocin (STZ). In the next eight weeks, the tumor carriers were treated with one of the IR/IGF1R antagonists penta-O-galloyl-[Formula: see text]-D-glucose (PGG) and epigallocatechin gallate (EGCG) or treated with vehicle. When pancreatic tumors were examined, their fraction occupied with living cells was decreased following STZ pretreatment and/or IR/IGF1R antagonism. Using Western blot, we examined tumor grafts for IR/IGF1R expression and activity. We also determined proteins that were downstream to IR/IGF1R and responsible for signal transduction, glycolysis, angiogenesis, and apoptosis. We demonstrated that STZ-induced decrease in intra-pancreatic insulin reduced IR/IGF1R expression and activity, decreased the proteins that promoted cell survival, and increased the proteins that promoted apoptosis. These suggest that intra-pancreatic insulin supported local cancer cells. When tumor carriers were treated with PGG or EGCG, the results were similar to those seen following STZ pretreatment. Thus, the biggest changes in examined proteins were usually seen when STZ pretreatment and PGG/EGCG treatment concurred. This suggests that intra-pancreatic insulin normally combated pharmacologic effects of PGG and EGCG. In conclusion, intra-pancreatic insulin nourishes pancreatic cancer cells and helps the cells resist IR/IGF1R antagonism.


Assuntos
Catequina/análogos & derivados , Taninos Hidrolisáveis/farmacologia , Insulina/fisiologia , Neoplasias Pancreáticas/patologia , Receptor de Insulina/antagonistas & inibidores , Animais , Catequina/farmacologia , Linhagem Celular Tumoral , Expressão Gênica/efeitos dos fármacos , Humanos , Insulina/metabolismo , Fator de Crescimento Insulin-Like I/genética , Fator de Crescimento Insulin-Like I/metabolismo , Masculino , Camundongos Nus , Receptor de Insulina/genética , Receptor de Insulina/metabolismo , Estreptozocina/farmacologia
12.
BMC Psychiatry ; 20(1): 208, 2020 05 08.
Artigo em Inglês | MEDLINE | ID: mdl-32384884

RESUMO

BACKGROUND: IGF-1 is an essential neurotrophin produced peripherally and in the brain. Impairments in the brain IGF-1 concentrations might be responsible for some aspects of major depressive disorder (MDD) pathogenesis, whereas peripheral IGF-1 could have the marker value. We aimed: 1) to compare serum IGF-1 levels in MDD patients and healthy controls (HC); 2) to elucidate possible associations between changes in IGF-1 expression and crucial characteristics of the current depressive episode, MDD course; 3) to evaluate IGF-1 dynamics after 8 weeks` vortioxetine treatment. METHODS: Seventy-eight MDD patients (according to DSM-5) and 47 HC were enrolled. Serum IGF-1, psychopathological (MADRS, CGI) and neuropsychological parameters (PDQ-5, RAVLT, TMT-B, DSST) were analyzed in all subjects at admission and 48 patients after 8 weeks` vortioxetine treatment. AUC-ROCs were calculated to determine if the value of serum IGF-1 could separate MDD patients from HC. Multiple regression models were performed to explore relationships between IGF-1 and depressive episode's symptoms. RESULTS: MDD patients had significantly higher serum IGF-1 levels than HC (228 (183-312) ng/ml vs 153 (129-186) ng/ml, p < 0.0001). IGF-1 had a good diagnostic value for predicting MDD in the whole sample with AUC of 0.820 (p < 0.0001). For a cutoff of 178.00 ng/ml, the sensitivity and specificity were 83 and 71%, respectively, and the number needed to misdiagnose was 5, indicating that only 1 of 5 tests give an invalid result. Among MADRS items, only reported sadness, inner tension, and concentration difficulties were significantly positively associated with serum IGF-1 concentrations. Vortioxetine treatment significantly attenuated IGF-1 levels and improved all psychopathological, neuropsychological parameters. CONCLUSIONS: Significant associations between IGF-1 levels and hypothymia, anxiety, and cognitive disturbances may indicate a pathogenic role of IGF-1 for the mentioned symptoms. We assume that the activity of the cerebral-hepatic axis increases in response to insufficient IGF-1 brain expression in MDD patients, whereas, vortioxetine treatment restores cerebral IGF-1 concentrations and, consequently, decreases its compensatory production by the liver. TRIAL REGISTRATION: registered at ClinicalTrials.gov (NCT03187093). First posted on 14th June 2017.


Assuntos
Transtorno Depressivo Maior/diagnóstico , Transtorno Depressivo Maior/tratamento farmacológico , Fator de Crescimento Insulin-Like I/metabolismo , Vortioxetina/uso terapêutico , Adulto , Biomarcadores/sangue , Estudos de Casos e Controles , Transtorno Depressivo Maior/sangue , Método Duplo-Cego , Feminino , Humanos , Fator de Crescimento Insulin-Like I/análise , Masculino , Reprodutibilidade dos Testes , Resultado do Tratamento
13.
Med Hypotheses ; 142: 109797, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32416411

RESUMO

The current pandemic of Covid-19 has created a paradigm for possibly gaining greater insight in two conditions:Studies since the beginning of this century have supported the view that IGF-1 deficiency in the neonate defines the basis of autism. As a result, it appears that interleukin-6 in corona virus-based infections causes reduced defenses because of suppressed IGF-1, especially in older patients. This may also portend an increase of autism in the offspring of gravidas currently affected severely by Covid-19.


Assuntos
Transtorno Autístico/complicações , Infecções por Coronavirus/complicações , Pneumonia Viral/complicações , Betacoronavirus , Biomarcadores/metabolismo , Aleitamento Materno , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Inflamação , Fator de Crescimento Insulin-Like I/deficiência , Fator de Crescimento Insulin-Like I/metabolismo , Interleucina-6/metabolismo , Pandemias , Gravidez , Complicações Infecciosas na Gravidez
14.
Mutat Res ; 784: 108307, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32430099

RESUMO

Insulin-like growth factor (IGF) system stimulates growth, proliferation, and regulates differentiation of cells in a tissue-specific manner. It is composed of two insulin-like growth factors (IGF-1 and IGF-2), six insulin-like growth factor-binding proteins (IGFBPs), and two insulin-like growth factor receptors (IGF-1R and IGF-2R). IGF actions take place mostly through the activation of the plasma membrane-bound IGF-Rs by the circulating ligands (IGFs) released from the IGFBPs that stabilize their levels in the serum. This review focuses on the IGF-1 part of the system. The IGF-1 gene, which is expressed mainly in the liver as well as in other tissues, comprises six alternatively spliced exons that code for three protein isoforms (pro-IGF-1A, pro-IGF-1B, and pro-IGF-1C), which are processed to mature IGF-1 and E-peptides. The IGF-1R undergoes autophosphorylation, resulting in a signaling cascade involving numerous cytoplasmic proteins such as AKT and MAPKs, which regulate the expression of target genes. However, a more complex picture of the axis has recently emerged with all its components being translocated to the nuclear compartment. IGF-1R takes part in the regulation of gene expression by forming transcription complexes, modifying the activity of chromatin remodeling proteins, and participating in DNA damage tolerance mechanisms. Four IGFBPs contain a nuclear localization signal (NLS), which targets them to the nucleus, where they regulate gene expression (IGFBP-2, IGFBP-3, IGFBP-5, IGFBP-6) and DNA damage repair (IGFBP-3 and IGFBP-6). Last but not least, the IGF-1B isoform has been reported to be localized in the nuclear compartment. However, no specific molecular actions have been assigned to the nuclear pro-IGF-1B or its derivative EB peptide. Therefore, further studies are needed to shed light on their nuclear activity. These recently uncovered nuclear actions of different components of the IGF-1 axis are relevant in cancer cell biology and are discussed in this review.


Assuntos
Núcleo Celular/genética , Dano ao DNA , Regulação da Expressão Gênica , Proteínas de Ligação a Fator de Crescimento Semelhante a Insulina/metabolismo , Fator de Crescimento Insulin-Like I/metabolismo , Animais , Humanos , Proteínas de Ligação a Fator de Crescimento Semelhante a Insulina/genética , Fator de Crescimento Insulin-Like I/genética , Transdução de Sinais
15.
Arch Anim Nutr ; 74(4): 325-342, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32362138

RESUMO

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


Assuntos
Galinhas/fisiologia , Glicerol/metabolismo , Fator de Crescimento Insulin-Like I/metabolismo , Intestinos/efeitos dos fármacos , Ração Animal/análise , Animais , Peso Corporal/efeitos dos fármacos , Galinhas/anatomia & histologia , Galinhas/crescimento & desenvolvimento , Dieta/veterinária , Glicerol/administração & dosagem , Injeções/veterinária , Fator de Crescimento Insulin-Like I/administração & dosagem , Intestinos/anatomia & histologia , Óvulo/efeitos dos fármacos
16.
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
17.
J Cardiovasc Pharmacol Ther ; 25(4): 338-345, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32323557

RESUMO

BACKGROUND: Vitamin D plays an important role in immune system and in the regulation of inflammatory cytokines. Coronary artery bypass graft (CABG) with cardiopulmonary bypass (CPB) is associated with an extensive inflammatory response. The aim of this study is to examine the effect of vitamin D treatment on the apoptosis and inflammatory changes developed after CABG. METHODS: This trial was conducted on 70 patients undergoing CABG with CPB. Patients were randomly administered either in placebo or in the group of orally consuming 150 000 IU vitamin D daily for 3 consecutive days before surgery. The right atrium sample was taken to assess caspases 2, 3, and 7 activity using immunohistochemistry method. The serum level of interleukin-10 (IL-10) and insulin-like growth factor 1 (IGF-1) were compared at intervals. RESULTS: The average number of positive cells for caspases 2 and 3 were less in vitamin D group (P = .006 and P < .001, respectively). There was an increase in serum levels of IL-10 after 3 days from vitamin D treatment before surgery (vitamin D group = 4.4 ± 4.9 ng/mL and control group = 1 ± 0.5 ng/mL, P = .001). After operation, IL-10 increased in both groups, higher level in vitamin D group (P < .001). The comparison of serum IGF-1 showed significant difference after 3 days (P = .006) and remained higher in vitamin D group after CPB (P < .001). CONCLUSIONS: These findings suggest the apoptosis rate after CPB can be reduced by vitamin D. Vitamin D treatment may improve the inflammatory status before and after surgery. Further studies are needed to confirm the antiapoptotic property of vitamin D and clinical implication.


Assuntos
Apoptose/efeitos dos fármacos , Ponte Cardiopulmonar/efeitos adversos , Ponte de Artéria Coronária/efeitos adversos , Suplementos Nutricionais , Átrios do Coração/efeitos dos fármacos , Vitamina D/administração & dosagem , Idoso , Biomarcadores/sangue , Caspases/metabolismo , Suplementos Nutricionais/efeitos adversos , Método Duplo-Cego , Feminino , Átrios do Coração/metabolismo , Átrios do Coração/patologia , Humanos , Mediadores da Inflamação/sangue , Fator de Crescimento Insulin-Like I/metabolismo , Interleucina-10/sangue , Irã (Geográfico) , Masculino , Pessoa de Meia-Idade , Fatores de Tempo , Resultado do Tratamento , Vitamina D/efeitos adversos
18.
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
19.
PLoS One ; 15(4): e0231972, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32320994

RESUMO

At present, a large number of studies have reported that hydrogen has antioxidant functions and prevents oxidative stress damage. However, it is not clear whether hydrogen can prolong longevity based on these effects. Therefore, we studied and explored the antiaging potential of exogenous hydrogen and its ability to extend longevity using Caenorhabditis elegans (C. elegans) as an animal model. Our results showed that the lifespans of the N2, sod-3 and sod-5 mutant strains were extended by approximately 22.7%, 9.5%, and 8.7%, respectively, after hydrogen treatment, but hydrogen had no effect on the lifespans of the daf-2 and daf-16 mutant strains. Meanwhile, the level of reactive oxygen species (ROS) in the hydrogen treatment group was significantly lower than that in the control group. At the transcript level, the expression of age-1 and let-363 was obviously decreased, while the expression of ins-18 was increased at the same time point (14 d). Compared with the control group, paraquat (PQ) could reduce the lifespan of the N2 and sod-5 mutant strains. Importantly, the longevity of these mutant strains recovered to normal levels when the animals were treated with exogenous hydrogen. According to these results, the lifespan of C. elegans is closely related to oxidative stress and can be significantly prolonged by reducing oxidative stress damage. Taken together, our data showed that hydrogen is a valuable antioxidant that can significantly reduce the body's ROS levels and extend the lifespan of C. elegans. This study also laid a foundation for the subsequent application of hydrogen in antiaging studies.


Assuntos
Caenorhabditis elegans/efeitos dos fármacos , Caenorhabditis elegans/fisiologia , Hidrogênio/farmacologia , Longevidade/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Animais , Caenorhabditis elegans/citologia , Caenorhabditis elegans/metabolismo , Regulação para Baixo/efeitos dos fármacos , Interações Medicamentosas , Insulina/metabolismo , Fator de Crescimento Insulin-Like I/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Paraquat/farmacologia , Transdução de Sinais/efeitos dos fármacos
20.
Cancer Invest ; 38(5): 289-299, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32308049

RESUMO

The aim was to evaluate the clinical impact of IGF-1/IGF-1R in Tunisian laryngeal carcinoma. A high IGF-1R immunohistochemical expression was found in our series (81.43%). A tendency toward an association between IGF-1R expression and lymph node metastasis was found (p = 0.068). Patients with positive IGF-1R expression showed a short disease free survival (p = 0.053) and a high recurrence rate. Furthermore, circulating IGF-1 levels sera, detected by ELISA, were higher among patients compared to controls (p < 0.001). IGF-1R might have a prognostic significance and could be a factor of tumor recurrence. However, high levels of IGF-1 increase the risk of developing of LSCC disease.


Assuntos
Fator de Crescimento Insulin-Like I/metabolismo , Neoplasias Laríngeas/metabolismo , Neoplasias Laríngeas/patologia , Receptor IGF Tipo 1/metabolismo , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patologia , Intervalo Livre de Doença , Feminino , Humanos , Imuno-Histoquímica/métodos , Metástase Linfática/patologia , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/metabolismo , Recidiva Local de Neoplasia/patologia , Prognóstico , Estudos Retrospectivos , Tunísia
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