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1.
Toxicol Lett ; 321: 44-53, 2020 Mar 15.
Artículo en Inglés | MEDLINE | ID: mdl-31811911

RESUMEN

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.


Asunto(s)
Dieta Alta en Grasa , Etanol/toxicidad , Glomerulonefritis/etiología , Glomérulos Renales/efectos de los fármacos , Efectos Tardíos de la Exposición Prenatal , Transducción de Señal/efectos de los fármacos , Animales , Femenino , Fibrosis , Regulación de la Expresión Génica , Edad Gestacional , Glomerulonefritis/genética , Glomerulonefritis/metabolismo , Glomerulonefritis/patología , Glucocorticoides/metabolismo , Factor I del Crecimiento Similar a la Insulina/genética , Factor I del Crecimiento Similar a la Insulina/metabolismo , Glomérulos Renales/metabolismo , Glomérulos Renales/patología , Masculino , Embarazo , Ratas Wistar , Receptor de Angiotensina Tipo 2/genética , Receptor de Angiotensina Tipo 2/metabolismo , Transducción de Señal/genética
2.
Int J Radiat Biol ; 96(1): 112-128, 2020 01.
Artículo en Inglés | MEDLINE | ID: mdl-30475652

RESUMEN

Purpose: Göttingen minipig (G-MP) displays classic gastrointestinal acute radiation syndrome (GI-ARS) following total body irradiation (TBI) at GI doses which are lethal by 10-14 days. In collaboration with BARDA, we are developing a hemi-body/partial body irradiation (PBI) model by exposing only the abdomen and lower extremities to study GI structure/function impairment, natural history of injury and recovery, as well as correlative biomarkers out to 30 days.Materials and methods: Twenty-four G-MP were exposed to either 12 or 16 Gy (LINAC Elekta); head, forelimbs, and thorax were outside the irradiation field, sparing ∼50% of the bone marrow. Animals were followed for 30 days with euthanasia scheduled at pre-set intervals to study the time course of GI injury and recovery. Hematological profiles, clinical symptoms, gross- and histo-pathology including markers of proliferation and apoptosis in the small intestines, gut function parameters (food tolerance, digestion, absorption, citrulline production), and levels of two biomarkers, CRP and IGF-1, were evaluated.Results: PBI at 16 Gy yielded higher lethality than 12 Gy. Unlike TBI, PBI did not cause severe pancytopenia or external hemorrhage, as expected, and allowed to focus the injury on GI organs while sparing the radiation sensitive heart and lung. Compromised animals showed inactivity, anorexia, vomiting, diarrhea, and weight loss. Histology revealed that in 12 Gy irradiated animals, lesions recovered overtime. In 16 Gy irradiated animals, lesions were more pronounced and persistent. BrdU and Ki67 labelling demonstrated dose-dependent loss of crypts and subsequent mucosal ulceration which recovered over time. Minimal apoptosis was observed at both doses. Reductions in food tolerance, digestion, absorption, and citrulline production were time and dose-dependent. Loss of citrulline reached a nadir between 6-12 days and then recovered partially. CRP and IGF-1 were upregulated following PBI at GI doses.Conclusions: This lower hemi-body irradiation model allowed for extended survival at GI-specific ARS doses and development of a well-controlled GI syndrome with minimal hematopoietic injury or confounding mortality from cardiopulmonary damage. A dose-dependent impairment in the intestinal structure resulted in overall decreased gut functionality followed by a partial recovery. However, while the structure appeared to be recovered, not all functionality was attained. PBI induced systemic inflammation and altered the IGF-1 hormone indicating that these can be used as biomarkers in the minipig even under partial body conditions. This PBI model aligns with other minipig models under BARDA's large animal consortium to test medical countermeasure efficacy against a less complex GI-specific ARS injury.


Asunto(s)
Síndrome de Radiación Aguda/patología , Síndrome de Radiación Aguda/fisiopatología , Tracto Gastrointestinal/fisiopatología , Tracto Gastrointestinal/efectos de la radiación , Síndrome de Radiación Aguda/sangre , Animales , Recuento de Células Sanguíneas , Proteína C-Reactiva/metabolismo , Citrulina/sangre , Digestión/efectos de la radiación , Modelos Animales de Enfermedad , Relación Dosis-Respuesta en la Radiación , Tracto Gastrointestinal/patología , Factor I del Crecimiento Similar a la Insulina/metabolismo , Masculino , Porcinos , Porcinos Enanos , Factores de Tiempo
3.
BMC Complement Altern Med ; 19(1): 324, 2019 Nov 21.
Artículo en Inglés | MEDLINE | ID: mdl-31752829

RESUMEN

BACKGROUND: The present study was designed to investigate the effects of Berberis vulgaris (BV) juice consumption on plasma levels of insulin-like growth factor (IGF-1), IGF-binding proteins (IGFBPs), and the expression of PPAR-γ, VEGF and HIF in women with benign breast disease. METHODS: This parallel design randomized, double-blind controlled clinical trial was conducted on 85 eligible patients diagnosed with benign breast disease. They were assigned randomly into either BV juice group (n = 44, BV juice: 480 ml/day) or placebo group (n = 41, BV placebo juice: 480 ml/day) for 8 weeks intervention. Participants, caregivers and those who assessed laboratory analyses were blinded to the assignments. Plasma levels of biomarkers were measured at baseline and after 8 weeks by ELISA. Quantitative real-time PCR was used to measure the fold change in the expression of each interested gene. RESULTS: The compliance of participants was 95.2% and 40 available subjects analyzed in each group at last. Relative treatment (RT) effects for BV juice caused 16% fall in IGF-1 concentration and 37% reduction in the ratio of IGF-1/1GFBP1. Absolute treatment effect expressed 111 ng/ml increased mean differences of IGFBP-3 between BV group and placebo. Plasma level of PPAR-γ increased in both groups but it was not significant. Fold changes in the expressions of PPAR-γ, VEGF and HIF showed down-regulation in the intervention group compared to placebos (P < 0.05). CONCLUSIONS: The BV juice intervention over 8 weeks was accompanied by acceptable efficacy and decreased plasma IGF-1, and IGF-1/IGFBP-1 ratio partly could be assigned to enhanced IGFBP-1 level in women with BBD. The intervention caused reductions in the expression levels of PPAR, VEGF, and HIF which are remarkable genomic changes to potentially prevent breast tumorigenesis. TRIAL REGISTRATION: IRCT2012110511335N2. Registered 10 July 2013 (retrospectively registered).


Asunto(s)
Berberis , Neoplasias de la Mama , Jugos de Frutas y Vegetales , Adulto , Mama/química , Mama/patología , Neoplasias de la Mama/química , Neoplasias de la Mama/dietoterapia , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Femenino , Humanos , Factor 1 Inducible por Hipoxia/análisis , Factor 1 Inducible por Hipoxia/metabolismo , Factor I del Crecimiento Similar a la Insulina/análisis , Factor I del Crecimiento Similar a la Insulina/metabolismo , Persona de Mediana Edad , PPAR gamma/análisis , PPAR gamma/metabolismo , Factor A de Crecimiento Endotelial Vascular/análisis , Factor A de Crecimiento Endotelial Vascular/metabolismo , Adulto Joven
4.
Biochemistry (Mosc) ; 84(10): 1213-1219, 2019 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-31694517

RESUMEN

Diabetes mellitus is characterized by increased platelet activation which is determined by many factors including changes in the expression of membrane proteins. The aim of this study was to investigate the sensitivity of human platelets to the insulin-like growth factor (IGF) system in patients with poorly controlled type 2 diabetes mellitus (DM2). Ligand binding was analyzed using 125I-labelled IGF-1 and insulin, and relative expression of insulin-like growth factor 1 receptor (IGF-1R) and insulin receptor (IR) was evaluated by Western blotting. Platelet aggregation in the presence of IGF-1 was studied by the plate aggregometry assay. We found that platelets from DM2 patients exhibited significantly higher IGF-1 binding and upregulation of IGF-1R expression in comparison with healthy individuals. Both insulin binding and IR expression were lower in the DM2 group, but the differences with the healthy control were statistically insignificant. The potentiating effect of IGF-1 on the thrombin-induced activation of platelets was detected in both groups but was significantly more pronounced in the DM2 patients. The initial rate of platelet activation in the presence of IGF-1 positively correlated with the concentration of glycated hemoglobin. Platelets isolated from DM2 patients displayed elevated expression of the IGF-1R subunits, which might have contributed to the higher sensitivity of these cells to IGF-1 in thrombin-initiated aggregation by increasing the rate of platelet activation. However, further experiments are needed to investigate the role of IGF-1 in thrombotic complications that usually accompany diabetes.


Asunto(s)
Plaquetas/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Factor I del Crecimiento Similar a la Insulina/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Factor I del Crecimiento Similar a la Insulina/aislamiento & purificación , Masculino , Persona de Mediana Edad
5.
Cell Physiol Biochem ; 53(5): 851-864, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31714043

RESUMEN

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.


Asunto(s)
Betaína/farmacología , Cyprinidae/metabolismo , Regulación de la Expresión Génica/efectos de los fármacos , Lisina/farmacología , Alimentación Animal , Animales , Catalasa/metabolismo , Cyprinidae/crecimiento & desarrollo , Ghrelina/genética , Ghrelina/metabolismo , Hormona Liberadora de Hormona del Crecimiento/genética , Hormona Liberadora de Hormona del Crecimiento/metabolismo , Factor I del Crecimiento Similar a la Insulina/genética , Factor I del Crecimiento Similar a la Insulina/metabolismo , Mucosa Intestinal/efectos de los fármacos , Mucosa Intestinal/metabolismo , Leptina/genética , Leptina/metabolismo , Hígado/enzimología , Hígado/metabolismo , Receptores de Ghrelina/genética , Receptores de Ghrelina/metabolismo , Superóxido Dismutasa/metabolismo
6.
Niger J Clin Pract ; 22(10): 1417-1422, 2019 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-31607733

RESUMEN

Background: There is a mutual dynamic interaction between thyroid volume (TV), insulin-like growth factor-1 (IGF-1), and body mass index (BMI). These covariates undergo a change with the transition into puberty. The heterogeneity of the variates and study populations complicate the evaluation of the role of pure pubertal effect. Objective: The purpose of this study was to investigate the effect of puberty on IGF-1 and TV in a predetermined homogenous population such as obese children. Subjects and Methods: Three hundred and eighty children (202 girls and 178 boys) aged between 6 and 18 were enrolled in this prospective study. The children were assigned to two groups according to their pubertal status, i.e., prepubertal (n = 169) and postpubertal (n = 211). According to age and sex, the obese group (n = 222) was made up of children at and above the 95th percentile, and the control group (n = 158) of children under the 85th percentile. The following parameters were evaluated in all children: BMI, pubertal status, TV, and serum IGF-1, IGFBP-3, and IGF-1:IGFBP-3 molar ratio. Results: In comparison to the prepubertal obese group, the obese group at Tanner stage 2 had a larger mean TV (P = 0.008) and higher IGF-1 level (P = 0.033). There was a positive correlation between IGF-1 and TV both in the prepubertal and pubertal group (r169= 0.369, P = 0.001; r211= 0.316, P = 0.004, respectively), whereas there was no correlation between IGF-1 and BMI (r169= 0.99, P = 0.092; r211= 0.094, P = 0.088, respectively). Conclusion: This study showed that the TV and serum IGF-1 levels were increased in obese children in the early stage of puberty and that there was a positive correlation between these two variables in all children, which shows the specific effect of the early stage of puberty on the increase in TV and IGF-1 levels and suggests that increased TV is associated with the increase in IGF-1 levels in a homogenous group such as obese children.


Asunto(s)
Factor I del Crecimiento Similar a la Insulina/metabolismo , Obesidad/sangre , Obesidad/fisiopatología , Pubertad/fisiología , Maduración Sexual , Glándula Tiroides/fisiología , Adolescente , Índice de Masa Corporal , Niño , Preescolar , Femenino , Humanos , Proteína 3 de Unión a Factor de Crecimiento Similar a la Insulina , Masculino , Estudios Prospectivos , Proteínas Recombinantes
7.
Int J Nanomedicine ; 14: 7921-7931, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31632009

RESUMEN

Purpose: We designed formulations based on minoxidil (MXD) nanoparticles (N-MXD) and examined whether N-MXD can increase drug delivery into the follicles. In addition, we investigated the effect of N-MXD on hair growth in C57BL/6 mice. Methods: N-MXD (1%) was prepared as follows: methylcellulose, p-hydroxyalkylbenzoates, mannitol, and MXD were dispersed in purified water and milled using zirconia beads under refrigeration (5500 rpm, 30 s×15 times, intermittent milling). C57BL/6 mice were used to evaluate hair-growth effects. The expression levels of mRNA and protein for vascular endothelial growth factor (VEGF) and insulin-like growth factor-1 (IGF-1) were determined by real-time PCR and ELISA methods, respectively. Results: The ratio of solid-MXD was approximately 60% in N-MXD, and the MXD nanoparticles (90-300 nm) were oblong in shape. For the design of nanomedicines, usability is important. Therefore, we measured the stability and toxicity after N-MXD treatment. No agglutination of MXD nanoparticles was detected for 2 weeks, and no redness or MXD powder residue was observed in the skin after repetitive applications of N-MXD. Next, we evaluated hair-growth effects by N-MXD treatment. MXD contents in the skin tissue from N-MXD were lower than for commercially available MXD formulations (CA-MXD). Conversely, MXD contents in the hair bulbs were higher for N-MXD than for CA-MXD, and the drug efficacy of N-MXD was also higher than that of CA-MXD. In addition, the mRNA and protein levels of IGF-1 and VEGF were enhanced by the repetitive application of N-MXD and CA-MXD, and the enhanced IGF-1 and VEGF levels were significantly higher for N-MXD than for CA-MXD. Conclusion: We designed a novel nanomedicine based on MXD nanoparticles and showed that N-MXD can deliver MXD into hair bulbs via hair follicles and that the therapeutic efficiency for hair growth is higher than for CA-MXD (solution type).


Asunto(s)
Sistemas de Liberación de Medicamentos , Cabello/crecimiento & desarrollo , Minoxidil/administración & dosificación , Minoxidil/farmacología , Nanopartículas/química , Animales , Cabello/efectos de los fármacos , Folículo Piloso/efectos de los fármacos , Folículo Piloso/crecimiento & desarrollo , Factor I del Crecimiento Similar a la Insulina/genética , Factor I del Crecimiento Similar a la Insulina/metabolismo , Masculino , Ratones Endogámicos C57BL , Minoxidil/sangre , Tamaño de la Partícula , ARN Mensajero/genética , ARN Mensajero/metabolismo , Piel/efectos de los fármacos , Solubilidad , Factor A de Crecimiento Endotelial Vascular/genética , Factor A de Crecimiento Endotelial Vascular/metabolismo
9.
Int J Mol Sci ; 20(18)2019 Sep 09.
Artículo en Inglés | MEDLINE | ID: mdl-31505893

RESUMEN

Persistent research over the past few decades has clearly established that the insulin-like family of growth factors, which is composed of insulin and insulin-like growth factors 1 (IGF1) and 2 (IGF2), plays essential roles in sexual development and reproduction of both males and females. Within the male and female reproductive organs, ligands of the family act in an autocrine/paracrine manner, in order to guide different aspects of gonadogenesis, sex determination, sex-specific development or reproductive performance. Although our knowledge has greatly improved over the last years, there are still several facets that remain to be deciphered. In this review, we first briefly outline the principles of sexual development and insulin/IGF signaling, and then present our current knowledge, both in rodents and humans, about the involvement of insulin/IGFs in sexual development and reproductive functions. We conclude by highlighting some interesting remarks and delineating certain unanswered questions that need to be addressed in future studies.


Asunto(s)
Factor II del Crecimiento Similar a la Insulina/metabolismo , Factor I del Crecimiento Similar a la Insulina/metabolismo , Insulina/metabolismo , Reproducción/fisiología , Diferenciación Sexual/fisiología , Transducción de Señal/fisiología , Animales , Femenino , Humanos , Masculino
10.
Nat Commun ; 10(1): 4427, 2019 09 27.
Artículo en Inglés | MEDLINE | ID: mdl-31562314

RESUMEN

Insulin and IGF-1 actions in vascular smooth muscle cells (VSMC) are associated with accelerated arterial intima hyperplasia and restenosis after angioplasty, especially in diabetes. To distinguish their relative roles, we delete insulin receptor (SMIRKO) or IGF-1 receptor (SMIGF1RKO) in VSMC and in mice. Here we report that intima hyperplasia is attenuated in SMIRKO mice, but not in SMIGF1RKO mice. In VSMC, deleting IGF1R increases homodimers of IR, enhances insulin binding, stimulates p-Akt and proliferation, but deleting IR decreases responses to insulin and IGF-1. Studies using chimeras of IR(extracellular domain)/IGF1R(intracellular-domain) or IGF1R(extracellular domain)/IR(intracellular-domain) demonstrate homodimer IRα enhances insulin binding and signaling which is inhibited by IGF1Rα. RNA-seq identifies hyaluronan synthase2 as a target of homo-IR, with its expression increases by IR activation in SMIGF1RKO mice and decreases in SMIRKO mice. Enhanced intima hyperplasia in diabetes is mainly due to insulin signaling via homo-IR, associated with increased Has2 expression.


Asunto(s)
Diabetes Mellitus/metabolismo , Hiperplasia/metabolismo , Resistencia a la Insulina/fisiología , Receptor IGF Tipo 1/metabolismo , Receptor de Insulina/metabolismo , Animales , Modelos Animales de Enfermedad , Arteria Femoral/lesiones , Arteria Femoral/metabolismo , Arteria Femoral/patología , Homocigoto , Hialuronano Sintasas/metabolismo , Insulina/metabolismo , Factor I del Crecimiento Similar a la Insulina/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Músculo Liso Vascular/metabolismo , Receptor IGF Tipo 1/química , Receptor de Insulina/química , Transducción de Señal
11.
J Dairy Sci ; 102(11): 10340-10359, 2019 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-31495618

RESUMEN

We have shown in 2 independent studies that cows who received recombinant bovine interleukin-8 (rbIL-8) administered intrauterinely shortly after parturition have a significant and long-lasting increase in milk yield. In the present study, we hypothesized that the increased milk production associated with rbIL-8 treatment is a consequence of increased postpartum dry matter intake (DMI) and orchestrated homeorhetic changes that prioritize milk production. Cows were enrolled into 1 of 3 treatment groups: those assigned to the control group (CTR; n = 70) received an intrauterine (IU) administration of 500 mL of Dulbecco's phosphate-buffered saline (DPBS) solution and 1 mL of DPBS solution intravenously (IV; jugular vein), those assigned to the rbIL-8 IV group (rbIL8-IV, n = 70) received an IV injection of 167 µg of rbIL-8 and 500 mL of DPBS solution IU, and cows assigned to the rbIL-8 IU group (rbIL8-IU, n = 70) received an IU administration with 1,195 µg of rbIL-8 diluted in 499.5 mL of DPBS solution and 1 mL of DPBS solution IV. Animals were housed in a tiestall from calving to 30 d in milk (DIM) to measure DMI. Blood samples were collected daily from calving to 7 DIM and weekly until 28 DIM. Insulin resistance was evaluated using an intravenous glucose tolerance test and intravenous insulin challenge test (IVICT) in a subgroup of cows (n = 20/treatment) at 10 and 11 DIM, respectively. Additionally, liver biopsy samples were taken at 14 DIM from the same subgroup of cows to measure triglyceride levels and cell proliferation and apoptosis. Cows treated with rbIL8-IU produced more milk (CTR = 36.9 ± 1.5; rbIL8-IU = 38.5 ± 1.5; rbIL8-IV = 36.6 ± 1.5 kg/d), energy-corrected milk (CTR = 42.9 ± 0.9; rbIL8-IU = 46.1 ± 0.8; rbIL8-IV = 43.7 ± 0.9 kg/d), and fat-corrected milk (CTR = 44.3 ± 0.9; rbIL8-IU = 47.8 ± 0.9; rbIL8-IV = 45.2 ± 0.9 kg/d) yields when compared with CTR cows, and no differences were observed between rbIL8-IV and CTR cows. The administration of rbIL8-IU significantly increased DMI compared with CTR (CTR = 18.8 ± 0.3; rbIL8-IU = 19.9 ± 0.3; rbIL8-IV = 19.3 ± 0.3 kg/d). Recombinant bIL-8 treatment did not affect glucose, insulin, or fatty acids (i.e., IVICT only) concentrations or their area under the curve in response to an intravenous glucose tolerance test and IVICT when compared with CTR. Moreover, rbIL-8 treatment administered IU or IV increased liver triglyceride levels. Additionally, cows treated with rbIL8-IU tended to have lower odds of developing hyperketonemia (odds ratio = 0.46, 95% confidence interval: 0.19 to 1.10), lower odds of clinical ketosis and displaced abomasum combined (odds ratio = 0.17, 95% confidence interval: 0.03 to 0.89), and lower odds of diseases combined (odds ratio = 0.43, 95% confidence interval: 0.21 to 0.86) when compared with CTR. We conclude that the administration of rbIL8-IU increases DMI, milk production, fat-corrected milk, and energy-corrected milk while improving overall health during the postpartum period. This study supports the use of rbIL-8 administered IU shortly after calving to improve health and production responses in lactating cows.


Asunto(s)
Bovinos/fisiología , Ingestión de Alimentos/efectos de los fármacos , Resistencia a la Insulina , Interleucina-8/administración & dosificación , Lactancia/efectos de los fármacos , Ácido 3-Hidroxibutírico/sangre , Animales , Apoptosis/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Dieta/veterinaria , Ácidos Grasos/metabolismo , Femenino , Glucosa/metabolismo , Hormona del Crecimiento/efectos de los fármacos , Hormona del Crecimiento/metabolismo , Insulina/sangre , Factor I del Crecimiento Similar a la Insulina/efectos de los fármacos , Factor I del Crecimiento Similar a la Insulina/metabolismo , Interleucina-8/metabolismo , Interleucina-8/farmacología , Cetosis/veterinaria , Lactancia/fisiología , Hígado/citología , Hígado/efectos de los fármacos , Leche/metabolismo , Parto , Periodo Posparto/sangre , Embarazo , Proteínas Recombinantes/administración & dosificación , Proteínas Recombinantes/metabolismo , Proteínas Recombinantes/farmacología
12.
Int J Mol Sci ; 20(17)2019 Aug 30.
Artículo en Inglés | MEDLINE | ID: mdl-31480400

RESUMEN

The insulin-like growth factor (IGF) pathway plays an important role in several brain tumor entities. However, the lack of inhibitors crossing the blood-brain barrier remains a significant obstacle for clinical translation. Here, we targeted the IGF pathway using ceritinib, an off-target inhibitor of the IGF1 receptor (IGF1R) and insulin receptor (INSR), in a pediatric patient with an unclassified brain tumor and a notch receptor 1 (NOTCH1) germline mutation. Pathway analysis of the tumor revealed activation of the sonic hedgehog (SHH), the wingless and integrated-1 (WNT), the IGF, and the Notch pathway. The proliferation of the patient tumor cells (225ZL) was inhibited by arsenic trioxide (ATO), which is an inhibitor of the SHH pathway, by linsitinib, which is an inhibitor of IGF1R and INSR, and by ceritinib. 225ZL expressed INSR but not IGF1R at the protein level, and ceritinib blocked the phosphorylation of INSR. Our first personalized treatment included ATO, but because of side effects, we switched to ceritinib. After 46 days, we achieved a concentration of 1.70 µM of ceritinib in the plasma, and after 58 days, MRI confirmed that there was a response to the treatment. Ceritinib accumulated in the tumor at a concentration of 2.72 µM. Our data suggest ceritinib as a promising drug for the treatment of IGF-driven brain tumors.


Asunto(s)
Neoplasias Encefálicas/tratamiento farmacológico , Factor I del Crecimiento Similar a la Insulina/metabolismo , Neoplasias Neuroepiteliales/tratamiento farmacológico , Pirimidinas/uso terapéutico , Sulfonas/uso terapéutico , Adulto , Trióxido de Arsénico/farmacología , Trióxido de Arsénico/uso terapéutico , Secuencia de Bases , Encéfalo/efectos de los fármacos , Encéfalo/patología , Neoplasias Encefálicas/patología , Línea Celular Tumoral , Preescolar , Aberraciones Cromosómicas , Metilación de ADN/genética , Femenino , Mutación de Línea Germinal/genética , Humanos , Terapia Molecular Dirigida , Neoplasias Neuroepiteliales/patología , Análisis de Componente Principal , Pirimidinas/farmacología , Receptor Notch1/metabolismo , Sulfonas/farmacología , Transcriptoma/genética , Proteína p53 Supresora de Tumor/genética
13.
BMC Vet Res ; 15(1): 315, 2019 Sep 02.
Artículo en Inglés | MEDLINE | ID: mdl-31477098

RESUMEN

BACKGROUND: Postbiotics have been established as potential feed additive to be used in monogastric such as poultry and swine to enhance health and growth performance. However, information on the postbiotics as feed additive in ruminants is very limited. The aim of this study was to elucidate the effects of supplementation of postbiotics in newly-weaned lambs on growth performance, digestibility, rumen fermentation characteristics and microbial population, blood metabolite and expression of genes related to growth and volatile fatty acid transport across the rumen epithelium. RESULTS: Postbiotic supplementation increased weight gain, feed intake, nutrient intake and nutrient digestibility of the lambs. No effect on ruminal pH and total VFA, whereas butyrate and ruminal ammonia-N concentration were improved. The lambs fed with postbiotics had higher blood total protein, urea nitrogen and glucose. However, no difference was observed in blood triglycerides and cholesterol levels. Postbiotics increased the population of fibre degrading bacteria but decreased total protozoa and methanogens in rumen. Postbiotics increased the mRNA expression of hepatic IGF-1 and ruminal MCT-1. CONCLUSIONS: The inclusion of postbiotics from L. plantarum RG14 in newly-weaned lambs improved growth performance, nutrient intake and nutrient digestibility reflected from better rumen fermentation and microbial parameters, blood metabolites and upregulation of growth and nutrient intake genes in the post-weaning lambs.


Asunto(s)
Suplementos Dietéticos , Factor I del Crecimiento Similar a la Insulina/metabolismo , Transportadores de Ácidos Monocarboxílicos/metabolismo , Receptores de Somatotropina/metabolismo , Ovinos/crecimiento & desarrollo , Alimentación Animal/análisis , Fenómenos Fisiológicos Nutricionales de los Animales , Animales , Dieta/veterinaria , Digestión , Fermentación , Regulación de la Expresión Génica/efectos de los fármacos , Factor I del Crecimiento Similar a la Insulina/genética , Lactobacillus plantarum , Masculino , Transportadores de Ácidos Monocarboxílicos/genética , Distribución Aleatoria , Receptores de Somatotropina/genética , Rumen/microbiología , Ovinos/sangre , Ovinos/metabolismo , Destete
14.
Anim Reprod Sci ; 208: 106134, 2019 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-31405461

RESUMEN

This study was conducted on 47 pluriparous pregnant Egyptian buffalo. Body condition score (BCS) was classified and blood samples were collected pre-partum and post-partum for estimation of IGF-1, hormonal, metabolic and antioxidants values. There was palpation per rectum and ultrasonography in addition to quantitation of progesterone (P4) and estradiol-17ß (E-17ß) for monitoring post-partum ovarian resumption. Reproductive indices were calculated 60, 90, 120 and 150 days post-partum. Based on the concentrations of P4 and E-17ß, buffalo were divided into ovulatory and non-ovulatory groups. The P4 and E-17ß were greater (P < 0.001) in ovulatory compared to non-ovulatory buffalo. The BCS and IGF-1 post-partum were greater (P =  0.024; 0.001, respectively) in ovulatory than non-ovulatory buffalo. Glucose and albumin were greater during pre- (P < 0.001; 0.013) and post-partum (P = 0.005; 0.003) periods in ovulatory than non-ovulatory buffalo. Post-partum, NEFA and BHBA concentrations were greater (P < 0.001) in non-ovulatory than ovulatory buffalo. The BUN concentrations were greater (P =  0.002) in non-ovulatory buffalo during pre- and post-partum periods. There were differences in GSH and SOD concentrations between groups (P < 0.001; 0.002, respectively). The BCS, albumin, IGF-1, GSH and SOD concentrations post-partum were negatively correlated with the delay of post-partum ovulation. The post-partum NEFA and BHBA concentrations, however, were positively correlated with delayed post-partum ovulation. Ovulatory buffalo had fewer (P < 0.01) days non-pregnant and for calving intervals as well as greater pregnancy rates than non-ovulatory buffalo. In conclusion, buffalo with delayed post-partum ovarian resumption were prone to have negative energy balance.


Asunto(s)
Antioxidantes/metabolismo , Búfalos/fisiología , Factor I del Crecimiento Similar a la Insulina/metabolismo , Ovario/fisiología , Periodo Posparto , Animales , Biomarcadores , Egipto , Estradiol/sangre , Estro , Femenino , Parto , Embarazo , Progesterona/sangre
15.
Int J Mol Sci ; 20(15)2019 Jul 31.
Artículo en Inglés | MEDLINE | ID: mdl-31370244

RESUMEN

Aneurysmal subarachnoid hemorrhage (aSAH), characterized by the extravasation of blood into the subarachnoid space caused by an intracranial aneurysm rupture, may lead to neurocognitive impairments and permanent disability and usually carries poor outcome. Dental or gingiva-derived stem cells have been shown to contribute to immune modulation and neuroregeneration, but the underlying mechanisms are unclear. In the present study, we sought to investigate whether dental pulp stem cells (DPSCs) secrete certain factor(s) that can ameliorate the neural damage and other manifestations in a rat aSAH model. Twenty-four hours after the induction of aSAH, microthrombosis, cortical vasoconstriction, and the decrease in microcirculation and tissue oxygen pressure were detected. Intrathecal administration of DPSC-derived conditioned media (DPSC-CM) ameliorated aSAH-induced vasoconstriction, neuroinflammation, and improved the oxygenation in the injured brain. Rotarod test revealed that the aSAH-induced cognitive and motor impairments were significantly improved by this DPSC-CM administration. Cytokine array indicated the major constituent of DPSC-CM was predominantly insulin growth factor-1 (IGF-1). Immunohistochemistry staining of injured brain tissue revealed the robust increase in Iba1-positive cells that were also ameliorated by DPSC-CM administration. Antibody-mediated neutralization of IGF-1 moderately deteriorated the rescuing effect of DPSC-CM on microcirculation, Iba1-positive cells in the injured brain area, and the cognitive/motor impairments. Taken together, the DPSC-derived secretory factors showed prominent therapeutic potential for aSAH. This therapeutic efficacy may include improvement of microcirculation, alleviation of neuroinflammation, and microglial activation; partially through IGF-1-dependent mechanisms.


Asunto(s)
Isquemia Encefálica/tratamiento farmacológico , Medios de Cultivo Condicionados/farmacología , Trastornos Neurocognitivos/tratamiento farmacológico , Fármacos Neuroprotectores/farmacología , Trastornos Psicomotores/tratamiento farmacológico , Hemorragia Subaracnoidea/tratamiento farmacológico , Trombosis/tratamiento farmacológico , Animales , Isquemia Encefálica/genética , Isquemia Encefálica/metabolismo , Isquemia Encefálica/fisiopatología , Proteínas de Unión al Calcio/genética , Proteínas de Unión al Calcio/metabolismo , Medios de Cultivo Condicionados/química , Pulpa Dental/citología , Pulpa Dental/metabolismo , Modelos Animales de Enfermedad , Expresión Génica , Inyecciones Espinales , Factor I del Crecimiento Similar a la Insulina/genética , Factor I del Crecimiento Similar a la Insulina/metabolismo , Masculino , Microcirculación/efectos de los fármacos , Proteínas de Microfilamentos/genética , Proteínas de Microfilamentos/metabolismo , Trastornos Neurocognitivos/genética , Trastornos Neurocognitivos/metabolismo , Trastornos Neurocognitivos/fisiopatología , Fármacos Neuroprotectores/química , Consumo de Oxígeno/efectos de los fármacos , Trastornos Psicomotores/genética , Trastornos Psicomotores/metabolismo , Trastornos Psicomotores/fisiopatología , Ratas , Ratas Wistar , Prueba de Desempeño de Rotación con Aceleración Constante , Células Madre/química , Células Madre/citología , Células Madre/metabolismo , Hemorragia Subaracnoidea/genética , Hemorragia Subaracnoidea/metabolismo , Hemorragia Subaracnoidea/fisiopatología , Trombosis/genética , Trombosis/metabolismo , Trombosis/fisiopatología , Vasoconstricción/efectos de los fármacos
16.
Plast Reconstr Surg ; 144(3): 623-632, 2019 09.
Artículo en Inglés | MEDLINE | ID: mdl-31461015

RESUMEN

BACKGROUND: Lipedema is characterized by localized accumulation of fat in the extremities, which is typically unresponsive to dietary regimens or physical activity. Although the disease is well described and has a high incidence, little is known regarding the molecular and cellular mechanisms underlying its pathogenesis. The aim of this study was to investigate the pathophysiology of lipedema adipose cells in vitro. METHODS: Adipose-derived stem cells were isolated from lipoaspirates derived from lipedema and nonlipedema patients undergoing tumescent liposuction. In vitro differentiation studies were performed for up to 14 days using adipogenic or regular culture medium. Supernatants and cell lysates were tested for adiponectin, leptin, insulin-like growth factor-1, aromatase (CYP19A1), and interleukin-8 content at days 7 and 14, using enzyme-linked immunosorbent assays. Adipogenesis was evaluated by visualizing and measuring cytoplasmic lipid accumulation. RESULTS: Lipedema adipose-derived stem cells showed impeded adipogenesis already at early stages of in vitro differentiation. Concomitant with a strongly reduced cytoplasmic lipid accumulation, significantly lower amounts of adiponectin and leptin were detectable in supernatants from lipedema adipose-derived stem cells and adipocytes compared with control cells. In addition, lipedema and nonlipedema cells differed in their expression of insulin-like growth factor-1, aromatase (CYP19A1), and interleukin-8 and in their proliferative activity. CONCLUSIONS: The authors' findings indicate that in vitro adipogenesis of lipedema adipose-derived stem cells is severely hampered compared with nonlipedema adipose-derived stem cells. Lipedema adipose cells differ not only in their lipid storage capacity but also in their adipokine expression pattern. This might serve as a valuable marker for diagnosis of lipedema, probably from an early stage on.


Asunto(s)
Adipocitos/metabolismo , Adipogénesis/fisiología , Tejido Adiposo/citología , Lipedema/patología , Células Madre/citología , Adiponectina/metabolismo , Tejido Adiposo/metabolismo , Adulto , Aromatasa/metabolismo , Biomarcadores/metabolismo , Diferenciación Celular/fisiología , Femenino , Humanos , Factor I del Crecimiento Similar a la Insulina/metabolismo , Células Madre/metabolismo
17.
Nat Commun ; 10(1): 3700, 2019 08 16.
Artículo en Inglés | MEDLINE | ID: mdl-31420552

RESUMEN

Little is known about the role of islet delta cells in regulating blood glucose homeostasis in vivo. Delta cells are important paracrine regulators of beta cell and alpha cell secretory activity, however the structural basis underlying this regulation has yet to be determined. Most delta cells are elongated and have a well-defined cell soma and a filopodia-like structure. Using in vivo optogenetics and high-speed Ca2+ imaging, we show that these filopodia are dynamic structures that contain a secretory machinery, enabling the delta cell to reach a large number of beta cells within the islet. This provides for efficient regulation of beta cell activity and is modulated by endogenous IGF-1/VEGF-A signaling. In pre-diabetes, delta cells undergo morphological changes that may be a compensation to maintain paracrine regulation of the beta cell. Our data provides an integrated picture of how delta cells can modulate beta cell activity under physiological conditions.


Asunto(s)
Islotes Pancreáticos/ultraestructura , Comunicación Paracrina , Estado Prediabético/patología , Seudópodos/ultraestructura , Células Secretoras de Somatostatina/ultraestructura , Animales , Glucemia/metabolismo , Humanos , Factor I del Crecimiento Similar a la Insulina/metabolismo , Células Secretoras de Insulina/citología , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/ultraestructura , Microscopía Intravital , Islotes Pancreáticos/citología , Islotes Pancreáticos/metabolismo , Islotes Pancreáticos/patología , Ratones , Ratones Transgénicos , Microscopía Electrónica , Imagen Óptica , Optogenética , Estado Prediabético/metabolismo , Seudópodos/metabolismo , Células Secretoras de Somatostatina/citología , Células Secretoras de Somatostatina/metabolismo , Factor A de Crecimiento Endotelial Vascular/metabolismo
18.
Artículo en Inglés | MEDLINE | ID: mdl-31461684

RESUMEN

Insulin-like growth factors (Igf1 and Igf2) play a key role in growth and development of vertebrates. In mammals, the expression of IGFs is regulated by estradiol-17ß (E2) via estrogen receptors (ESRs). The expression of igfs can also be regulated by E2 in fish, while comparative study of this is still lacking. The present study examined tissue distribution of igfs and hepatic expression of igfs and esrs during gonad development in Scatophagus argus by real-time PCR. Serum E2 concentration was measured by enzyme-linked immunosorbent assay (ELISA). The hepatic expression of igfs and esrs at gonadal phase III, incubated with either E2 (0.1, 1 or 10 µM) alone or in combination with estrogen receptor antagonists-fulvestrant, MPP or PHTPP, was measured. igf1 and igf2 expressed highest in liver of both sexes. Igf1, esr1 and esr2b expressions and serum E2 concentration increased, while igf2 and esr2a expressions decreased, during ovary development. Igfs and esrs expressions increased while serum E2 concentration maintained low during testis development. In females, E2 incubation enhanced the expressions of igf1 and esr1 but inhibited that of igf2 and esr2a. Both fulvestrant and MPP inhibited up-regulation effect of E2 on igf1 and esr1. Fulvestrant enhanced down-regulation effect of E2 on igf2 and esr2a, but MPP conversely. In males, E2 incubation enhanced the expressions of igfs, esr1 and esr2a. Fulvestrant and MPP inhibited up-regulation effect of E2 on igfs and esr1. PHTPP inhibited igf1 and esr2 expressions in both sexes. Our results indicated that the expression of igfs is regulated by E2 via Esrs in S. argus.


Asunto(s)
Estradiol/metabolismo , Peces/metabolismo , Factor II del Crecimiento Similar a la Insulina/metabolismo , Factor I del Crecimiento Similar a la Insulina/metabolismo , Receptores de Estradiol/metabolismo , Animales , Ensayo de Inmunoadsorción Enzimática , Femenino , Proteínas de Peces/metabolismo , Peces/crecimiento & desarrollo , Hígado/crecimiento & desarrollo , Hígado/metabolismo , Masculino , Ovario/crecimiento & desarrollo , Ovario/metabolismo , Testículo/crecimiento & desarrollo , Testículo/metabolismo
19.
Asia Pac J Ophthalmol (Phila) ; 8(4): 319-323, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31369407

RESUMEN

PURPOSE: The aims of this study were to correlate diabetic retinopathy (DR) changes with insulin-like growth factor 1 (IGF-1) levels in patients with type 1 diabetes of pubertal age group and to correlate the level of retinopathy with IGF-1 levels. METHODS: This cross-sectional study was done over 2 years and involved patients with type 1 diabetes of age 8 to 25 years. Patients presenting to Ophthalmology OPD and inpatient department along with active recruitment from old pediatrics and endocrinology records were taken for the study. Fasting serum IGF-1 was calculated using enzyme-linked immunosorbent assay technique. Fasting blood sugar levels were taken. Detailed ophthalmic examination was done and DR was noted in all the patients and correlated with IGF-1 levels. RESULTS: A total of 46 patients with type 1 diabetes were recruited into the study. The mean age of the patients was 14.33 ±â€Š4.36 years, with a female-to-male ratio of 3:2. No relationship of IGF-1 with age of onset of diabetes (P = 0.7) or fasting capillary blood glucose (CBG) (P = 0.6) was found, but a significant relationship was found with duration of diabetes (P = 0.001) and low IGF-1 levels (P < 0.0001). CONCLUSIONS: Severity of DR in patients with type 1 diabetes is inversely related to serum IGF-1 levels. Low IGF levels are an indicator for closer follow-up and strict management of diabetes and retinopathy.


Asunto(s)
Diabetes Mellitus Tipo 1/complicaciones , Retinopatía Diabética/sangre , Factor I del Crecimiento Similar a la Insulina/metabolismo , Pubertad , Adolescente , Adulto , Biomarcadores/sangre , Glucemia/metabolismo , Niño , Estudios Transversales , Diabetes Mellitus Tipo 1/sangre , Retinopatía Diabética/etiología , Ensayo de Inmunoadsorción Enzimática , Femenino , Humanos , Masculino , Adulto Joven
20.
Int J Mol Sci ; 20(16)2019 Aug 15.
Artículo en Inglés | MEDLINE | ID: mdl-31443143

RESUMEN

Rehmanniae Radix Praeparata (RR, named as Shudihuang in traditional Chinese medicine), the steamed roots of Rehmannia glutinosa Libosch (Scrophulariaceae), has been demonstrated to have anti-diabetic and anti-osteoporotic activities. This study aimed to explore the protective effect and underlying mechanism of RR on diabetes-induced bone loss. It was found that RR regulated the alkaline phosphatase activity and osteocalcin level, enhanced bone mineral density, and improved the bone microarchitecture in diabetic rats. The catalpol (CAT), acteoside (ACT), and echinacoside (ECH) from RR increased the proliferation and differentiation of osteoblastic MC3T3-E1 cells injured by high glucose and promoted the production of IGF-1 and expression of related proteins in BMP and IGF-1/PI3K/mammalian target of rapamycin complex 1 (mTOR) signaling pathways. The verifying tests of inhibitors of BMP pathway (noggin) and IGF-1/PI3K/mTOR pathway (picropodophyllin) and molecular docking of IGF-1R further indicated that CAT, ACT, and ECH extracted from RR enhanced bone formation by regulating IGF-1/PI3K/mTOR signaling pathways. These findings suggest that RR may prove to be a promising candidate drug for the prevention and treatment of diabetes-induced osteoporosis.


Asunto(s)
Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Experimental/metabolismo , Factor I del Crecimiento Similar a la Insulina/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Extractos Vegetales/uso terapéutico , Rehmannia/química , Serina-Treonina Quinasas TOR/metabolismo , Animales , Western Blotting , Densidad Ósea/efectos de los fármacos , Diferenciación Celular/efectos de los fármacos , Línea Celular , Diabetes Mellitus Experimental/inducido químicamente , Femenino , Factor I del Crecimiento Similar a la Insulina/genética , Masculino , Simulación del Acoplamiento Molecular , Osteocalcina/metabolismo , Osteogénesis/efectos de los fármacos , Osteoporosis/tratamiento farmacológico , Osteoporosis/metabolismo , Fosfatidilinositol 3-Quinasas/genética , Extractos Vegetales/química , Ratas , Ratas Wistar , Estreptozocina/toxicidad , Serina-Treonina Quinasas TOR/genética , Microtomografía por Rayos X
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