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1.
Neurochem Res ; 47(7): 2076-2089, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-35657460

RESUMO

BACKGROUND: Spinal cord injury (SCI) is a devastating neurological event that leads to severe motor and sensory dysfunction. Exosome-mediated transfer of circular RNAs (circRNAs) was associated with SCI, and exosomes have been reported to be produced by mesenchymal stem cells (MSCs). This study is designed to explore the mechanism of exosomal circZFHX3 on LPS-induced MSCs injury in SCI. METHODS: Exosomes were detected by transmission electron microscope and nanoparticle tracking analysis. CD9, CD63, CD81, and TSC101, B-cell lymphoma-2 (Bcl-2), Bcl-2 related X protein (Bax), Cleaved caspase 3, and Insulin-like growth factor 1 (IGF-1) protein levels were measured by western blot assay. CircZFHX3, microRNA-16-5p (miR-16-5p), and IGF-1 level were detected by real-time quantitative polymerase chain reaction (RT-qPCR). Cell viability and apoptosis were detected by Cell Counting Kit-8 (CCK-8) and flow cytometry assay. Levels of IL-1ß, IL-6, and TNF-α were assessed using Enzyme-linked immunosorbent assays (ELISA). ROS, LDH, and SOD levels were measured by the special kits. The binding between miR-16-5p and circZFHX3 or IGF-1 was predicted by Starbase and DianaTools and then verified by a dual-luciferase reporter and RNA Immunoprecipitation (RIP) assays. The biological role of exosomal circZFHX3 on SCI mice was examined in vivo. RESULTS: CircZFHX3 and IGF-1 were decreased, and miR-16-5p was increased in SCI mice. Also, exosomal circZFHX3 boosted cell viability and repress apoptosis, inflammation, and oxidative stress in LPS-treated BV-2 cells in vitro. Mechanically, circZFHX3 acted as a sponge of miR-16-5p to regulate IGF-1 expression. Exosomal circZFHX3 reduced cell injury of SCI in vivo. CONCLUSIONS: Exosomal circZFHX3 inhibited LPS-induced BV-2 cell injury partly by regulating the miR-16-5p/ IGF-1 axis, hinting at a promising therapeutic strategy for the SCI treatment.


Assuntos
Exossomos , Células-Tronco Mesenquimais , MicroRNAs , Traumatismos da Medula Espinal , Animais , Exossomos/metabolismo , Fator de Crescimento Insulin-Like I , Lipopolissacarídeos , Células-Tronco Mesenquimais/metabolismo , Camundongos , MicroRNAs/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Traumatismos da Medula Espinal/metabolismo
2.
In Vitro Cell Dev Biol Anim ; 58(5): 384-395, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35648337

RESUMO

The cell proliferation of bovine mammary epithelial cells (BMECs) and consequent milk synthesis are regulated by multiple factors. The purpose of this study was to examine the effect of 14-3-3ß on cellular proliferation and milk fat/ß-casein synthesis in BMECs and reveal its underlying mechanisms. In this study, we employed gene function analysis to explore the regulatory effect and molecular mechanisms of 14-3-3ß on milk synthesis and proliferation in BMECs. We found that leucine and IGF-1 enhance cell proliferation and milk synthesis in a 14-3-3ß-dependent manner and only exhibiting such effect in the presence of 14-3-3ß. We further determined that 14-3-3ß interacts with the IGF1R self-phosphorylation site and it additionally mediated leucine and IGF-1 to stimulate the synthesis of milk through the IGF1R-AKT-mTORC1 signaling pathway. In summary, our data indicated that 14-3-3ß mediates the expression of milk fat and protein stimulated by leucine and IGF-1, leading to lactogenesis through IGF1R signaling pathway in BMECs.


Assuntos
Glândulas Mamárias Animais , Leite , Animais , Bovinos , Células Epiteliais/metabolismo , Fator de Crescimento Insulin-Like I , Leucina/metabolismo , Leucina/farmacologia , Glândulas Mamárias Animais/metabolismo , Leite/metabolismo , Transdução de Sinais
3.
Growth Horm IGF Res ; 64: 101470, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35688068

RESUMO

OBJECTIVE: Anorexia nervosa (AN) is a severe mental disorder that is characterized by restriction of energy intake, low weight, and endocrine abnormalities. One of the known endocrine changes in relation to underweight is in the GH/IGF-I axis. The aim of the study was (a) to investigate longitudinal characteristics of the IGF-I-change during therapy and weight gain in adult AN, (b) to determine relationships between IGF-I and leptin, (c) to characterize patients with weak and pronounced hormonal reactions to underweight. DESIGN: Data was assessed from 19 AN patients. Over the first two months, serum IGF-I concentrations were assessed on a weekly basis; thereafter on a monthly basis. The trend of IGF-I values over time was analyzed using individual growth models. RESULTS: In total, n = 177 IGF-I measurements were analyzed. IGF-I increased significantly dependent on BMI (slope = 20.81, p < 0.001), not modulated by duration of disease. The increase in IGF-I was significantly related to the increase in leptin concentrations over time (slope = 15.57, p < 0.001). Patients with a weaker hormonal reaction to underweight were significantly older compared to patients with a pronounced hormonal reaction (t(17) = 3.07, p = 0.007). CONCLUSIONS: During treatment, IGF-I change is clearly related to BMI as well as to leptin. Age appears to be associated with the IGF-I response to underweight.


Assuntos
Anorexia Nervosa , Leptina , Adulto , Anorexia Nervosa/complicações , Anorexia Nervosa/terapia , Índice de Massa Corporal , Humanos , Pacientes Internados , Fator de Crescimento Insulin-Like I , Magreza/complicações
4.
J Hematol Oncol ; 15(1): 82, 2022 Jun 16.
Artigo em Inglês | MEDLINE | ID: mdl-35710446

RESUMO

Much higher risk of cancer has been found in diabetes patients. Insulin receptor (IR) and insulin-like growth factor 1 receptor (IGF1R) have been extensively studied in both breast cancer and diabetes therapies. Interestingly, a recent study proposed that IR/IGF1R ratio is an important factor for breast cancer prognosis. Women with higher IR/IGF1R ratio showed poor breast cancer prognosis as well as hyperinsulinemia. Here, we propose a novel mechanism that oncogenic protein TRIP-Br1 renders breast cancer cells and insulin deficient mice to have higher IR/IGF1R ratio by positively and negatively regulating IR and IGF1R expression at the protein level, respectively. TRIP-Br1 repressed IR degradation by suppressing its ubiquitination. Meanwhile, TRIP-Br1 directly interacts with both IGF1R and NEDD4-1 E3 ubiquitin ligase, in which TRIP-Br1/NEDD4-1 degrades IGF1R via ubiquitin/proteasome system. TRIP-Br1-mediated higher IR/IGF1R ratio enhanced the proliferation and survival of breast cancer cells. In conclusion, current study may provide an important information in the regulatory mechanism of how breast cancer cells have acquired higher IR/IGF1R ratio.


Assuntos
Neoplasias da Mama , Fator de Crescimento Insulin-Like I , Animais , Neoplasias da Mama/metabolismo , Feminino , Humanos , Fator de Crescimento Insulin-Like I/metabolismo , Camundongos , Prognóstico , Receptor IGF Tipo 1 , Receptor de Insulina , Ubiquitina
5.
Cell Mol Life Sci ; 79(7): 376, 2022 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-35731367

RESUMO

MicroRNAs (miRNAs) are short non-coding RNAs, highly conserved between species, that are powerful regulators of gene expression. Aberrant expression of miRNAs alters biological processes and pathways linked to human disease. miR-486-5p is a muscle-enriched miRNA localized to the cytoplasm and nucleus, and is highly abundant in human plasma and enriched in small extracellular vesicles. Studies of malignant and non-malignant diseases, including kidney diseases, have found correlations with circulating miR-486-5p levels, supporting its role as a potential biomarker. Pre-clinical studies of non-malignant diseases have identified miR-486-5p targets that regulate major signaling pathways involved in cellular proliferation, migration, angiogenesis, and apoptosis. Validated miR-486-5p targets include phosphatase and tensin homolog (PTEN) and FoXO1, whose suppression activates phosphatidyl inositol-3-kinase (PI3K)/Akt signaling. Targeting of Smad1/2/4 and IGF-1 by miR-486-5p inhibits transforming growth factor (TGF)-ß and insulin-like growth factor-1 (IGF-1) signaling, respectively. Other miR-486-5p targets include matrix metalloproteinase-19 (MMP-19), Sp5, histone acetyltransferase 1 (HAT1), and nuclear factor of activated T cells-5 (NFAT5). In this review, we examine the biogenesis, regulation, validated gene targets and biological effects of miR-486-5p in non-malignant diseases.


Assuntos
Fenômenos Biológicos , MicroRNAs , Proliferação de Células/genética , Humanos , Fator de Crescimento Insulin-Like I , MicroRNAs/genética , MicroRNAs/metabolismo , Transdução de Sinais/genética , Fator de Crescimento Transformador beta
6.
Adipocyte ; 11(1): 366-378, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-35734881

RESUMO

High fat diet (HFD)-induced obesity leads to perturbation in the storage function of white adipose tissue (WAT) resulting in deposition of lipids in tissues ill-equipped to deal with this challenge. The role of insulin like growth factor-1 (IGF-1) in the systemic and organ-specific responses to HFD is unclear. Using cixutumumab, a monoclonal antibody that internalizes and degrades cell surface IGF-1 receptors (IGF-1 R), leaving insulin receptor expression unchanged we aimed to establish the role of IGF-1 R in the response to a HFD. Mice treated with cixutumumab fed standard chow developed mild hyperinsulinemia with no change in WAT. When challenged by HFD mice treated with cixutumumab had reduced weight gain, reduced WAT expansion, and reduced hepatic lipid vacuole formation. In HFD-fed mice, cixutumumab led to reduced levels of genes encoding proteins important in fatty acid metabolism in WAT and liver. Cixutumumab protected against blunting of insulin-stimulated phosphorylation of Akt in liver of HFD fed mice. These data reveal an important role for IGF-1 R in the WAT and hepatic response to short-term nutrient excess. IGF-1 R inhibition during HFD leads to a lipodystrophic phenotype with a failure of WAT lipid storage and protection from HFD-induced hepatic insulin resistance.


Assuntos
Resistência à Insulina , Fator de Crescimento Insulin-Like I , Tecido Adiposo/metabolismo , Tecido Adiposo Branco/metabolismo , Animais , Anticorpos Monoclonais Humanizados , Dieta Hiperlipídica/efeitos adversos , Insulina/metabolismo , Fator de Crescimento Insulin-Like I/metabolismo , Lipídeos , Fígado/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/etiologia , Obesidade/metabolismo
7.
Eur J Pharmacol ; 927: 175067, 2022 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-35654135

RESUMO

The cell proliferation effect of S-allyl-L-cysteine (SAC) and its mechanisms were examined in primary cultures of adult rat hepatocytes. In serum-free cultivation, SAC (10-6 M)-stimulated hepatocytes showed significant proliferation compared to control at 5-h culture; the effect was dependent on the culture time and the dose of SAC (EC50 value 8.58 × 10-8 M). In addition, SAC-stimulated hepatocytes significantly increased mRNA expression levels of c-Myc and c-Fos at 1 h and cyclin B1 at 3.5 and 4 h, respectively. In contrast, alliin and allicin, structural analogs of SAC, did not show these effects observed with SAC. The SAC-induced hepatocyte proliferation effects were completely suppressed by monoclonal antibodies against growth hormone receptor and insulin-like growth factor type-I (IGF-I) receptor, respectively. Furthermore, the Janus kinase 2 (JAK2) inhibitor TG101209, phospholipase C (PLC) inhibitor U-73122, IGF-I receptor tyrosine kinase (RTK) inhibitor AG538, PI3 kinase inhibitor LY294002, MEK inhibitor PD98059, and mTOR inhibitor rapamycin completely suppressed the SAC-induced hepatocyte proliferation. JAK2 (p125 kDa) phosphorylation in cultured hepatocytes peaked 5 min after SAC stimulation. SAC-induced IGF-I RTK (p95 kDa) and ERK2 (p42 kDa) phosphorylation had slower rises than JAK2, peaking at 20 and 30 min, respectively. These results indicate that SAC promoted cell proliferation by growth hormone receptor/JAK2/PLC pathway activation followed by activation of the IGF-I RTK/PI3K/ERK2/mTOR pathway in primary cultures of adult rat hepatocytes.


Assuntos
Fator de Crescimento Insulin-Like I , Receptor IGF Tipo 1 , Animais , Proliferação de Células , Células Cultivadas , Cisteína/farmacologia , Hepatócitos , Fator de Crescimento Insulin-Like I/metabolismo , Fator de Crescimento Insulin-Like I/farmacologia , Janus Quinase 2/metabolismo , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Fosforilação , Ratos , Receptor IGF Tipo 1/metabolismo , Receptores da Somatotropina/metabolismo , Serina-Treonina Quinases TOR/metabolismo
8.
Sci Rep ; 12(1): 9633, 2022 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-35688844

RESUMO

Reproductive dysfunctions (RDs) characterized by impairment in testicular parameters, and metabolic disorders such as insulin resistance and type 2 diabetes mellitus (T2DM) are on the rise among human immunodeficiency virus (HIV) patients under tenofovir disoproxil fumarate (TDF) and highly active antiretroviral therapy (HAART). These adverse effects require a nanoparticle delivery system to circumvent biological barriers and ensure adequate ARVDs to viral reservoir sites like testis. This study aimed to investigate the effect of TDF-loaded silver nanoparticles (AgNPs), TDF-AgNPs on sperm quality, hormonal profile, insulin-like growth factor 1 (IGF-1), and testicular ultrastructure in diabetic rats, a result of which could cater for the neglected reproductive and metabolic dysfunctions in HIV therapeutic modality. Thirty-six adult Sprague-Dawley rats were assigned to diabetic and non-diabetic (n = 18). T2DM was induced by fructose-streptozotocin (Frt-STZ) rat model. Subsequently, the rats in both groups were subdivided into three groups each (n = 6) and administered distilled water, TDF, and TDF-AgNP. In this study, administration of TDF-AgNP to diabetic rats significantly reduced (p < 0.05) blood glucose level (268.7 ± 10.8 mg/dL) from 429 ± 16.9 mg/dL in diabetic control and prevented a drastic reduction in sperm count and viability. More so, TDF-AgNP significantly increased (p < 0.05) Gonadotropin-Releasing Hormone (1114.3 ± 112.6 µg), Follicle Stimulating Hormone (13.2 ± 1.5 IU/L), Luteinizing Hormone (140.7 ± 15.2 IU/L), testosterone (0.2 ± 0.02 ng/L), and IGF-1 (1564.0 ± 81.6 ng/mL) compared to their respective diabetic controls (383.4 ± 63.3, 6.1 ± 1.2, 76.1 ± 9.1, 0.1 ± 0.01, 769.4 ± 83.7). Also, TDF-AgNP treated diabetic rats presented an improved testicular architecture marked with the thickened basement membrane, degenerated Sertoli cells, spermatogenic cells, and axoneme. This study has demonstrated that administration of TDF-AgNPs restored the function of hypothalamic-pituitary-gonadal axis, normalized the hormonal profile, enhanced testicular function and structure to alleviate reproductive dysfunctions in diabetic rats. This is the first study to conjugate TDF with AgNPs and examined its effects on reproductive indices, local gonadal factor and testicular ultrastructure in male diabetic rats with the potential to cater for neglected reproductive dysfunction in HIV therapeutic modality.


Assuntos
Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2 , Infecções por HIV , Nanopartículas Metálicas , Animais , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Infecções por HIV/tratamento farmacológico , Humanos , Fator de Crescimento Insulin-Like I/metabolismo , Masculino , Ratos , Ratos Sprague-Dawley , Prata/farmacologia , Tenofovir/uso terapêutico , Testículo/metabolismo
9.
BMJ Open ; 12(6): e045776, 2022 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-35705353

RESUMO

OBJECTIVE: To assess the association of insulin-like growth factor 1 (IGF-1) with the risk of incident ischaemic stroke and outcome after ischaemic stroke. DESIGN: A systematic review of primary studies. SETTING: Hospitals in Western Sweden, Italy, China and Denmark. METHODS: A search was carried out in eligible studies in electronic databases (PubMed, Scopus, Embase, China National Knowledge Infrastructure and Web of Science) updated to 29 December 2020. The relevant data were extracted in order to conduct the meta-analysis. Review Manager V.5.2 was used to pool data and calculate the mean difference (MD) and its 95% CI. Heterogeneity, subgroup analysis, sensitivity analysis and publication bias were also performed in this meta-analysis. RESULTS: A total of 2277 patients were included in 17 studies. This meta-analysis indicated that higher serum IGF-1 levels were significantly correlated with less risk of ischaemic stroke (MD=-45.32 95% CI -63.70 to -26.94], p < 0.00001, I2=99%) and better improvement of outcome after ischaemic stroke (MD=27.52, 95% CI 3.89 to 51.14, p=0.02, I2=96%). According to subgroup analysis, heterogeneity comes from country, sample size, male and the time from symptom onset to blood collection. Sensitivity analysis showed that there was no significant influence of any individual study on the pooled MD. The effect of high heterogeneity on result credibility was eliminated when four included studies were merged (MD=-30.32, 95% CI -36.52 to -24.11, p< 0.00001, I2=0%). Moreover, no potential publication bias was discovered in this meta-analysis. CONCLUSION: Higher serum IGF-1 was significantly correlated with a lower risk of ischaemic stroke. In view of the high degree of heterogeneity, it may need more studies to confirm the prognostic value of serum IGF-1 levels in ischaemic stroke and explore the sources of heterogeneity.


Assuntos
Isquemia Encefálica , AVC Isquêmico , Acidente Vascular Cerebral , Humanos , Fator de Crescimento Insulin-Like I , Itália , Masculino
10.
Food Funct ; 13(12): 6830-6842, 2022 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-35687102

RESUMO

Vitamin D3 (VD3) has been reported to improve the reproductive performance of sows. This study was conducted to investigate the long-term effect of maternal VD3 supplementation during gestation on the intestinal health of piglets. Twenty-three Landrace × Yorkshire gilts were randomly allocated into two groups to receive one of the following two diets during gestation: basal diet (CON group, 800 IU VD3 per kg diet, n = 12) and VD3 supplemented diet (VD3 group, 2000 IU VD3 per kg diet, n = 11). All sows were then fed with the same diet during lactation. Results showed that maternal VD3 supplementation during lactation tended to decrease (p = 0.08) the body weight loss of sows during lactation compared to the CON group. Besides, the relative length and weight of the small intestine (SI) and the villus height of the duodenum and ileum in weaning piglets were much higher (p < 0.05) in the VD3 group than those in the CON group, though their body weight was not changed. Meanwhile, maternal VD3 supplementation significantly upregulated the expression levels of IGF-1, IGF-2R, VDR, GLUT-2 and CAT1 in the duodenum (p < 0.05), and increased the expression levels of IGF-1, IGF-1R, IGF-2R, VDR, Occludin, ZO-1, MUC2, PEPT1 and CAT1 (p < 0.05) in the jejunum of suckling piglets compared with the CON group. Besides, the concentration of SigA in the jejunum of suckling piglets was higher (p < 0.05) in the VD3 group than that in the CON group. In addition, maternal VD3 supplementation significantly increased the contents of short chain fatty acids and the relative abundance of Lactobacillus and Faecalibacterium (p < 0.05) in the feces of weaning piglets compared to the CON group. Moreover, the relative abundance of unidentified_Lachnospiraceae in the feces of weaning piglets tended to be higher (p = 0.05), while that of unidentified_Spirochaetaceae was lower (p < 0.05) in the VD3 group than those in the CON group. Taken together, maternal VD3 supplementation during gestation could improve the intestinal function and microbiota in suckling piglets.


Assuntos
Ração Animal , Fator de Crescimento Insulin-Like I , Ração Animal/análise , Animais , Dieta/veterinária , Suplementos Nutricionais , Feminino , Lactação , Gravidez , Suínos , Desmame
11.
Oncogene ; 41(25): 3385-3393, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35597813

RESUMO

The insulin-like growth factors (IGFs) and their regulatory proteins-IGF receptors and binding proteins-are strongly implicated in cancer progression and modulate cell survival and proliferation, migration, angiogenesis and metastasis. By regulating the bioavailability of the type-1 IGF receptor (IGF1R) ligands, IGF-1 and IGF-2, the IGF binding proteins (IGFBP-1 to -6) play essential roles in cancer progression. IGFBPs also influence cell communications through pathways that are independent of IGF1R activation. Noncoding RNAs (ncRNAs), which encompass a variety of RNA types including microRNAs (miRNAs) and long-noncoding RNAs (lncRNAs), have roles in multiple oncogenic pathways, but their many points of intersection with IGF axis functions remain to be fully explored. This review examines the functional interactions of miRNAs and lncRNAs with IGFs and their binding proteins in cancer, and reveals how the IGF axis may mediate ncRNA actions that promote or suppress cancer. A better understanding of the links between ncRNA and IGF pathways may suggest new avenues for prognosis and therapeutic intervention in cancer. Further, by exploring examples of intersecting ncRNA-IGF pathways in non-cancer conditions, it is proposed that new opportunities for future discovery in cancer control may be generated.


Assuntos
MicroRNAs , Neoplasias , RNA Longo não Codificante , Humanos , Proteínas de Ligação a Fator de Crescimento Semelhante a Insulina/genética , Proteínas de Ligação a Fator de Crescimento Semelhante a 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 , MicroRNAs/genética , Neoplasias/genética , RNA Longo não Codificante/genética , RNA não Traduzido/genética , Receptores de Somatomedina/metabolismo
12.
Cells ; 11(10)2022 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-35626647

RESUMO

A woman's endocrine system plays a crucial role in orchestrating cellular interactions throughout her life. The growth hormone (GH) and insulin-like growth factor (IGF) system appears to impact crucial reproductive events and cell types of the ovary, such as granulosa cells, theca cells, and oocytes. Further, IGF1 is a cornerstone during embryonic development and influences predominantly developing and pre-antral follicles. In this commentary, we will emphasize the pleiotropic effects of IGF1 on physiological processes inside the egg. Herein, we will provide a brief overview on IGF1 related cell signal transduction pathways during the maturation and aging of oocytes. We aim to elucidate from a molecular and biochemical point of view if IGF1 in women with metabolic imbalances such as obesity or diabetes could be used in clinics as a novel, reliable estimator for the developmental competence of an oocyte.


Assuntos
Oócitos , Folículo Ovariano , Feminino , Células da Granulosa/fisiologia , Hormônio do Crescimento/farmacologia , Humanos , Fator de Crescimento Insulin-Like I/farmacologia , Folículo Ovariano/fisiologia , Ovário
13.
Cells ; 11(10)2022 05 12.
Artigo em Inglês | MEDLINE | ID: mdl-35626664

RESUMO

Normal growth and development in mammals are tightly controlled by numerous genetic factors and metabolic conditions. The growth hormone (GH)-insulin-like growth factor-1 (IGF1) hormonal axis is a key player in the regulation of these processes. Dysregulation of the GH-IGF1 endocrine system is linked to a number of pathologies, ranging from growth deficits to cancer. Laron syndrome (LS) is a type of dwarfism that results from mutation of the GH receptor (GHR) gene, leading to GH resistance and short stature as well as a number of metabolic abnormalities. Of major clinical relevance, epidemiological studies have shown that LS patients do not develop cancer. While the mechanisms associated with cancer protection in LS have not yet been elucidated, genomic analyses have identified a series of metabolic genes that are over-represented in LS patients. We hypothesized that these genes might constitute novel targets for IGF1 action. With a fold-change of 11.09, UDP-glucuronosyltransferase 2B15 (UGT2B15) was the top up-regulated gene in LS. The UGT2B15 gene codes for an enzyme that converts xenobiotic substances into lipophilic compounds and thereby facilitates their clearance from the body. We investigated the regulation of UGT2B15 gene expression by IGF1 and insulin. Both hormones inhibited UGT2B15 mRNA levels in endometrial and breast cancer cell lines. Regulation of UGT2B15 protein levels by IGF1/insulin, however, was more complex and not always correlated with mRNA levels. Furthermore, UGT2B15 expression was dependent on p53 status. Thus, UGT2B15 mRNA levels were higher in cell lines expressing a wild-type p53 compared to cells containing a mutated p53. Animal studies confirmed an inverse correlation between UGT2B15 and p53 levels. In summary, increased UGT2B15 levels in LS might confer upon patient's protection from genotoxic damage.


Assuntos
Glucuronosiltransferase/metabolismo , Síndrome de Laron , Neoplasias , Animais , Glucuronosiltransferase/genética , Glicosiltransferases/metabolismo , Hormônio do Crescimento/metabolismo , Humanos , Insulina/metabolismo , Fator de Crescimento Insulin-Like I/metabolismo , Síndrome de Laron/genética , Síndrome de Laron/metabolismo , Mamíferos/metabolismo , Neoplasias/metabolismo , RNA Mensageiro/genética , Proteína Supressora de Tumor p53/genética , Difosfato de Uridina
14.
Clin Nutr ; 41(6): 1272-1280, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35504170

RESUMO

BACKGROUND & AIMS: Insulin and insulin-like growth factor (IGF)-1 signaling is a proposed mechanism linking dietary protein and major chronic diseases. However, it is unclear whether animal and plant proteins are associated with biomarkers of insulin and IGF axis. METHODS: We analyzed a total of 14,709 participants from Nurses' Health Study and Health Professionals Follow-up Study who had provided a blood sample. Detailed dietary information was assessed using validated food frequency questionnaires. We assessed C-peptide, insulin, IGF-1, and IGF binding proteins (BP). Multivariable-adjusted linear regressions were used to examine associations of animal and plant protein intake with biomarkers after adjusting for confounders. RESULTS: The medians (5th-95th percentiles) of animal and plant protein intake (% of total energy) were 13% (8-19%) and 5% (4-7%), respectively. Compared to participants in the lowest quintile, those in the highest quintile of animal protein had 4.8% (95% CI: 1.9, 7.9; P-trend<0.001) higher concentration of IGF-1 and -7.2% (95% CI: -14.8, 1.1; P for trend = 0.03) and -11.8% (95% CI: -20.6, -1.9; P-trend<0.001) lower concentration of IGFBP-1 and IGFBP-2, respectively, after adjustment for major lifestyle factors and diet quality. In contrast, no association was observed between animal protein intake and C-peptide, insulin and IGFBP-3. The associations were restricted to participants with at least one unhealthy lifestyle risk factor (i.e., overweight/obese, physical inactivity, smoking, and heavy alcohol intake). Plant protein tended to be strongly associated with numerous biomarkers in age-adjusted analyses but these became largely attenuated or non-significant in multivariable adjustment. Plant protein intake remained positively associated with IGF-1 (P-trend = 0.002) and possibly IGFBP-1 (P-trend = 0.02) after multivariable adjustment. Substitution of plant protein with animal protein sources was associated with lower IGFBP-1. In additional analysis, IGF-1 and IGFBPs were estimated to mediate approximately 5-20% of the association between animal protein and type 2 diabetes. CONCLUSIONS: Higher animal protein intake was associated with higher IGF-1 and lower IGFBP-1 and IGFBP-2, whereas higher plant protein intake was associated with higher IGF-1 and IGFBP-1.


Assuntos
Diabetes Mellitus Tipo 2 , Proteínas na Dieta , Proteínas Animais da Dieta , Animais , Biomarcadores/sangue , Peptídeo C/sangue , Diabetes Mellitus Tipo 2/sangue , Proteínas na Dieta/sangue , Seguimentos , Humanos , Insulina/sangue , Insulina/metabolismo , Proteínas de Ligação a Fator de Crescimento Semelhante a Insulina/sangue , Fator de Crescimento Insulin-Like I/metabolismo , Proteínas de Vegetais Comestíveis
15.
Cells ; 11(10)2022 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-35626678

RESUMO

Insulin-like growth factor-I (IGF-I) signaling plays a key role in learning and memory. IGF-I increases the spiking and induces synaptic plasticity in the mice barrel cortex (Noriega-Prieto et al., 2021), favoring the induction of the long-term potentiation (LTP) by Spike Timing-Dependent Protocols (STDP) (Noriega-Prieto et al., 2021). Here, we studied whether these IGF-I effects depend on endocannabinoids (eCBs) and nitric oxide (NO). We recorded both excitatory postsynaptic currents (EPSCs) and inhibitory postsynaptic currents (IPSCs) evoked by stimulation of the basal dendrites of layer II/III pyramidal neurons of the Barrel Cortex and analyzed the effect of IGF-I in the presence of a CB1R antagonist, AM251, and inhibitor of the NO synthesis, L-NAME, to prevent the eCBs and the NO-mediated signaling. Interestingly, L-NAME abolished any modulatory effect of the IGF-I-induced excitatory and inhibitory transmission changes, suggesting the essential role of NO. Surprisingly, the inhibition of CB1Rs did not only block the potentiation of EPSCs but reversed to a depression, highlighting the remarkable functions of the eCB system. In conclusion, eCBs and NO play a vital role in deciding the sign of the effects induced by IGF-I in the neocortex, suggesting a neuromodulatory interplay among IGF-I, NO, and eCBs.


Assuntos
Endocanabinoides , Óxido Nítrico , Animais , Endocanabinoides/farmacologia , Endocanabinoides/fisiologia , Fator de Crescimento Insulin-Like I/farmacologia , Camundongos , NG-Nitroarginina Metil Éster , Plasticidade Neuronal/fisiologia
16.
Growth Horm IGF Res ; 64: 101468, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35605565

RESUMO

OBJECTIVE: Decathlon is a combined track and field competition, consisting of ten, mainly anaerobic events. Insulin-like growth factor-I (IGF1) axis plays a pivotal role in athletes' structural and functional muscle adaptation to exercise training, and in their competitive performance. Based on the great demand for speed physiological characteristics among decathlon athletes, the aim of this study was to assess the prevalence of IGF genetic polymorphisms among decathletes, to present an optimal genetic profile for enhancing performance. METHODS: The participants included 151 male athletes and 75 male non-athletic controls from Israel and Estonia. Athletes were divided into four groups, according to the field of expertise: (a) 40 sprinters and long jumpers; (b) 40 middle distance runners; (c) 44 Weightlifters; and (d) 27 decathletes. Genomic DNA was extracted from the participants' buccal epithelial cells using standard protocol and then analyzed for IGF1 axis related genetic polymorphism using the allelic discrimination assay. RESULTS: A significantly higher prevalence of the IGF1 rs35767 TT genotype was found among decathletes compared to the other athletes, as well as a lower prevalence of the IGF1 rs7136446 GG genotype, a higher prevalence of the IGF1R rs1464430 AA genotype, and a higher prevalence of the IGF2 rs680 GG genotype. Moreover, among the decathletes, carriers of the IGF1 rs7136446 GG genotype achieved higher decathlon scores compared to A-allele carriers. CONCLUSIONS: The findings of this study suggest a potential beneficial role for some IGF-axis polymorphisms (mainly the IGF1 1245 TT and the IGF2 GG) among decathletes, both of which are associated with improved speed performance.


Assuntos
Desempenho Atlético , Fator de Crescimento Insulin-Like I , Atletas , Desempenho Atlético/fisiologia , Genótipo , Humanos , Fator de Crescimento Insulin-Like I/genética , Masculino , Polimorfismo Genético , Prevalência
17.
Circulation ; 145(25): 1853-1866, 2022 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-35616058

RESUMO

BACKGROUND: The insulin-like growth factor 1 (IGF1) pathway is a key regulator of cellular metabolism and aging. Although its inhibition promotes longevity across species, the effect of attenuated IGF1 signaling on cardiac aging remains controversial. METHODS: We performed a lifelong study to assess cardiac health and lifespan in 2 cardiomyocyte-specific transgenic mouse models with enhanced versus reduced IGF1 receptor (IGF1R) signaling. Male mice with human IGF1R overexpression or dominant negative phosphoinositide 3-kinase mutation were examined at different life stages by echocardiography, invasive hemodynamics, and treadmill coupled to indirect calorimetry. In vitro assays included cardiac histology, mitochondrial respiration, ATP synthesis, autophagic flux, and targeted metabolome profiling, and immunoblots of key IGF1R downstream targets in mouse and human explanted failing and nonfailing hearts, as well. RESULTS: Young mice with increased IGF1R signaling exhibited superior cardiac function that progressively declined with aging in an accelerated fashion compared with wild-type animals, resulting in heart failure and a reduced lifespan. In contrast, mice with low cardiac IGF1R signaling exhibited inferior cardiac function early in life, but superior cardiac performance during aging, and increased maximum lifespan, as well. Mechanistically, the late-life detrimental effects of IGF1R activation correlated with suppressed autophagic flux and impaired oxidative phosphorylation in the heart. Low IGF1R activity consistently improved myocardial bioenergetics and function of the aging heart in an autophagy-dependent manner. In humans, failing hearts, but not those with compensated hypertrophy, displayed exaggerated IGF1R expression and signaling activity. CONCLUSIONS: Our findings indicate that the relationship between IGF1R signaling and cardiac health is not linear, but rather biphasic. Hence, pharmacological inhibitors of the IGF1 pathway, albeit unsuitable for young individuals, might be worth considering in older adults.


Assuntos
Fator de Crescimento Insulin-Like I , Longevidade , Idoso , Animais , Promoção da Saúde , Humanos , Fator de Crescimento Insulin-Like I/metabolismo , Masculino , Camundongos , Miócitos Cardíacos/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Receptor IGF Tipo 1/genética , Receptor IGF Tipo 1/metabolismo
18.
Animal ; 16(5): 100527, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35500509

RESUMO

Enhanced early life nutrition stimulates the functionality of the hypothalamic-pituitary-testicular (HPT) biochemical signalling axis, resulting in precocious reproductive development in bull calves. Additionally, there is evidence that peptides and hormones produced within adipose tissue depots are also central in mediating the effect of metabolic status with reproductive development. The objective of this study was to undertake gene co-expression analyses on transcriptional data of the HPT and adipose tissues derived from bull calves fed contrasting planes of nutrition up to 18 weeks of life. The relationship between networks of co-expressed genes in each tissue dataset with calf phenotypic data was also assessed using a Pearson correlation analysis. Phenotypic data were related to metabolic status (systemic concentrations of insulin, leptin, adiponectin and IGF-1) reproductive development (systemic concentrations of testosterone, FSH and LH) and markers of testicular development (seminiferous tubule diameter, seminiferous tubule lumen score, spermatogenic cells and Sertoli cells). In the hypothalamus, gene co-expression networks involved in biochemical signalling processes related to gonadotropin-releasing hormone (GnRH) secretion were positively associated (P < 0.05) with systemic concentrations of IGF-1 and insulin. Similarly, a network of gene transcripts involved in GnRH signalling in the anterior pituitary was positively associated (P < 0.05) with systemic concentrations of LH. In the testes and adipose tissues, networks of co-expressed genes implicated in cholesterol and fatty acid biosynthesis were positively associated (P < 0.05) with lumen score, Sertoli cell number, and stage of spermatogenesis. Additionally, gene co-expression networks significantly associated (P < 0.05) with both metabolic and reproductive trait data were found to be enriched (P < 0.05) for biological pathways related to energy production, cellular growth and proliferation, GnRH signalling and cholesterol biosynthesis across multiple tissues examined. Results from this study highlight networks of co-expressed genes directly associated with markers of enhanced metabolic status and subsequent earlier reproductive development. Furthermore, genes involved in biological processes mentioned above may hold potential for informing genomic selection breeding programmes for the selection of calves capable of displaying earlier reproductive development as a consequence of enhanced dietary intake.


Assuntos
Fator de Crescimento Insulin-Like I , Insulinas , Animais , Bovinos , Colesterol/metabolismo , Hormônio Liberador de Gonadotropina/genética , Hormônio Liberador de Gonadotropina/metabolismo , Fator de Crescimento Insulin-Like I/genética , Fator de Crescimento Insulin-Like I/metabolismo , Insulinas/metabolismo , Masculino , Estado Nutricional , Testículo , Testosterona/metabolismo
19.
Cells ; 11(9)2022 05 02.
Artigo em Inglês | MEDLINE | ID: mdl-35563827

RESUMO

Essential amino acids (EAAs) are those that cannot be synthesized enough to meet organismal demand; therefore, it is believed that they must be taken from the diet for optimal growth. The growth hormone (GH)/insulin-like growth factor-I (IGF-I) system is also considered significant for growth regulation in mammals. This study aimed to evaluate the relative contributions of protein nutrition and the GH/IGF-I system to body growth regulation. Experiments using rodents and hepatocyte-derived cell lines subjected to EAA deficiency showed that a reduction in the serum EAA concentration hinders Igf1 transcription in the liver in a cell-autonomous manner, thereby decreasing serum IGF-I levels. Remarkably, when the serum IGF-I level of mice on a low-protein diet was restored by the recombinant IGF-I infusion, the body growth was mostly rescued, although the mice were still deficient in EAA intake. Meanwhile, the GH signal activation and subsequent Igf1 transcription were also dramatically diminished by EAA deprivation in the cell culture model. Altogether, we demonstrate that EAAs are not strictly necessary for animal growth as building blocks but are required as IGF-I-tropic cues. The results will bring a paradigm shift regarding the definition of "essential" amino acids.


Assuntos
Hormônio do Crescimento , Fator de Crescimento Insulin-Like I , Aminoácidos Essenciais/metabolismo , Animais , Dieta com Restrição de Proteínas , Hormônio do Crescimento/metabolismo , Fator de Crescimento Insulin-Like I/metabolismo , Fígado/metabolismo , Mamíferos/metabolismo , Camundongos
20.
Clinics (Sao Paulo) ; 77: 100051, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35636162

RESUMO

OBJECTIVES: Some previous studies indicated that the excessive proliferation and migration of Pulmonary Artery Smooth Muscle Cells (PASMCs) could be observed in pulmonary artery intima after Pulmonary Embolism (PE) occurred. In addition, recent studies identified some miRNAs that are differentially expressed in the blood of PE patients, which might be used as a diagnostic biomarker for PE, including let-7a-5p, let-7b-5p, and miR-150-5p. Hence, the authors sought to explore the effects of let-7b-5p in PASMC proliferation and migration and the corresponding regulatory mechanism. METHODS: Platelet-Derived Growth Factor (PDGF) was utilized to induce the hyper-proliferation model in PASMCs. The mRNA and protein expression levels were detected by RT-qPCR and western blot, respectively. The proliferation of PASMCs was evaluated by the detection of PCNA expression, as well as CCK-8 and Edu assays. Wound healing and Transwell assays were exploited to assess the migration ability of PASMCs. The targets of let-7b-5p were predicted based on two bioinformatics online tools. Dual-luciferase and Ago2 pull-down assays were applied to confirm the interaction between let-7b-5p and IGF1. RESULTS: 40 ng/mL PDGF was selected as the optimal concentration to induce PASMCs. let-7b-5p mimics suppressed the proliferation and migration of PDGF-induced PASMCs, while let-7b-5p inhibitor led to the opposite result. In further mechanism exploration, IGF1 was predicted and confirmed as the direct target gene of let-7b-5p. The promotion role of IGF1 overexpression on the proliferation and migration of PDGF-induced PASMCs was dramatically countered by let-7b-5p mimics. CONCLUSION: let-7b-5p prohibits the proliferation and migration of PDGF-induced PASMCs by modulating IGF1.


Assuntos
MicroRNAs/genética , Artéria Pulmonar , Proliferação de Células , Humanos , Fator de Crescimento Insulin-Like I/genética , Fator de Crescimento Insulin-Like I/farmacologia , Miócitos de Músculo Liso/metabolismo , Artéria Pulmonar/metabolismo , RNA Mensageiro/metabolismo
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