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1.
Molecules ; 26(12)2021 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-34199327

RESUMO

The application of insulin-like growth factor 1 (IGF-1) to the round window membrane (RWM) is an emerging treatment for inner ear diseases. RWM permeability is the key factor for efficient IGF-1 delivery. Ultrasound microbubbles (USMBs) can increase drug permeation through the RWM. In the present study, the enhancing effect of USMBs on the efficacy of IGF-1 application and the treatment effect of USMB-mediated IGF-1 delivery for noise-induced hearing loss (NIHL) were investigated. Forty-seven guinea pigs were assigned to three groups: the USM group, which received local application of recombinant human IGF-1 (rhIGF-1, 10 µg/µL) following application of USMBs to the RWM; the RWS group, which received IGF-1 application alone; and the saline-treated group. The perilymphatic concentration of rhIGF-1 in the USM group was 1.95- and 1.67- fold of that in the RWS group, 2 and 24 h after treatment, respectively. After 5 h of 118 dB SPL noise exposure, the USM group had the lowest threshold shift in auditory brainstem response, least loss of cochlear outer hair cells, and least reduction in the number of synaptic ribbons on postexposure day 28 among the three groups. The combination of USMB and IGF-1 led to a better therapeutic response to NIHL. Two hours after treatment, the USM group had significantly higher levels of Akt1 and Mapk3 gene expression than the other two groups. The most intense immunostaining for phosphor-AKT and phospho-ERK1/2 was detected in the cochlea in the USM group. These results suggested that USMB can be applied to enhance the efficacy of IGF-1 therapy in the treatment of inner ear diseases.


Assuntos
Cóclea/efeitos dos fármacos , Sistemas de Liberação de Medicamentos/métodos , Perda Auditiva Provocada por Ruído/tratamento farmacológico , Fator de Crescimento Insulin-Like I/farmacologia , Microbolhas/uso terapêutico , Janela da Cóclea/efeitos dos fármacos , Ondas Ultrassônicas , Animais , Cóclea/metabolismo , Modelos Animais de Doenças , Cobaias , Perda Auditiva Provocada por Ruído/metabolismo , Perda Auditiva Provocada por Ruído/patologia , Janela da Cóclea/metabolismo
2.
Int J Mol Sci ; 22(12)2021 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-34200896

RESUMO

The goals of this study are to develop a high purity patented silk fibroin (SF) film and test its suitability to be used as a slow-release delivery for insulin-like growth factor-1 (IGF-1). The release rate of the SF film delivering IGF-1 followed zero-order kinetics as determined via the Ritger and Peppas equation. The release rate constant was identified as 0.11, 0.23, and 0.09% h-1 at 37 °C for SF films loaded with 0.65, 6.5, and 65 pmol IGF-1, respectively. More importantly, the IGF-1 activity was preserved for more than 30 days when complexed with the SF film. We show that the IGF-1-loaded SF films significantly accelerated wound healing in vitro (BALB/3T3) and in vivo (diabetic mice), compared with wounds treated with free IGF-1 and an IGF-1-loaded hydrocolloid dressing. This was evidenced by a six-fold increase in the granulation tissue area in the IGF-1-loaded SF film treatment group compared to that of the PBS control group. Western blotting analysis also demonstrated that IGF-1 receptor (IGF1R) phosphorylation in diabetic wounds increased more significantly in the IGF-1-loaded SF films group than in other experimental groups. Our results suggest that IGF-1 sustained release from SF films promotes wound healing through continuously activating the IGF1R pathway, leading to the enhancement of both wound re-epithelialization and granulation tissue formation in diabetic mice. Collectively, these data indicate that SF films have considerable potential to be used as a wound dressing material for long-term IGF-1 delivery for diabetic wound therapy.


Assuntos
Bombyx/química , Diabetes Mellitus Experimental/fisiopatologia , Sistemas de Liberação de Medicamentos , Fibroblastos/efeitos dos fármacos , Fibroínas/química , Fator de Crescimento Insulin-Like I/administração & dosagem , Cicatrização/efeitos dos fármacos , Animais , Bandagens , Preparações de Ação Retardada , Feminino , Fator de Crescimento Insulin-Like I/farmacologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Reepitelização , Receptores para Leptina/fisiologia
3.
Int J Mol Sci ; 22(10)2021 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-34063554

RESUMO

Acute lung injury (ALI) afflicts approximately 200,000 patients annually and has a 40% mortality rate. The COVID-19 pandemic has massively increased the rate of ALI incidence. The pathogenesis of ALI involves tissue damage from invading microbes and, in severe cases, the overexpression of inflammatory cytokines such as tumor necrosis factor-α (TNF-α) and interleukin-1ß (IL-1ß). This study aimed to develop a therapy to normalize the excess production of inflammatory cytokines and promote tissue repair in the lipopolysaccharide (LPS)-induced ALI. Based on our previous studies, we tested the insulin-like growth factor I (IGF-I) and BTP-2 therapies. IGF-I was selected, because we and others have shown that elevated inflammatory cytokines suppress the expression of growth hormone receptors in the liver, leading to a decrease in the circulating IGF-I. IGF-I is a growth factor that increases vascular protection, enhances tissue repair, and decreases pro-inflammatory cytokines. It is also required to produce anti-inflammatory 1,25-dihydroxyvitamin D. BTP-2, an inhibitor of cytosolic calcium, was used to suppress the LPS-induced increase in cytosolic calcium, which otherwise leads to an increase in proinflammatory cytokines. We showed that LPS increased the expression of the primary inflammatory mediators such as toll like receptor-4 (TLR-4), IL-1ß, interleukin-17 (IL-17), TNF-α, and interferon-γ (IFN-γ), which were normalized by the IGF-I + BTP-2 dual therapy in the lungs, along with improved vascular gene expression markers. The histologic lung injury score was markedly elevated by LPS and reduced to normal by the combination therapy. In conclusion, the LPS-induced increases in inflammatory cytokines, vascular injuries, and lung injuries were all improved by IGF-I + BTP-2 combination therapy.


Assuntos
Lesão Pulmonar Aguda/tratamento farmacológico , Lesão Pulmonar Aguda/metabolismo , Anilidas/farmacologia , Citocinas/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Fator de Crescimento Insulin-Like I/farmacologia , Tiadiazóis/farmacologia , Lesão Pulmonar Aguda/patologia , Lesão Pulmonar Aguda/virologia , Anilidas/uso terapêutico , Animais , COVID-19/complicações , Cálcio/metabolismo , Canais de Cálcio/metabolismo , Citocinas/genética , Modelos Animais de Doenças , Feminino , Regulação da Expressão Gênica/genética , Imuno-Histoquímica , Fator de Crescimento Insulin-Like I/metabolismo , Fator de Crescimento Insulin-Like I/uso terapêutico , Interferon gama/genética , Interferon gama/metabolismo , Interleucina-17/genética , Interleucina-17/metabolismo , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Lipopolissacarídeos/toxicidade , Camundongos , Camundongos Endogâmicos C57BL , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Tiadiazóis/uso terapêutico , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/metabolismo , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo
4.
Cell Death Dis ; 12(6): 564, 2021 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-34075028

RESUMO

Metastasis is the major reason for the high mortality of colorectal cancer (CRC) patients and its molecular mechanism remains unclear. Here, we report a novel role of Homeobox A13 (HOXA13), a member of the Homeobox (HOX) family, in promoting CRC metastasis. The elevated expression of HOXA13 was positively correlated with distant metastasis, higher AJCC stage, and poor prognosis in two independent CRC cohorts. Overexpression of HOXA13 promoted CRC metastasis whereas downregulation of HOXA13 suppressed CRC metastasis. Mechanistically, HOXA13 facilitated CRC metastasis by transactivating ATP-citrate lyase (ACLY) and insulin-like growth factor 1 receptor (IGF1R). Knockdown of ACLY and IGFIR inhibited HOXA13-medicated CRC metastasis, whereas ectopic overexpression of ACLY and IGFIR rescued the decreased CRC metastasis induced by HOXA13 knockdown. Furthermore, Insulin-like growth factor 1 (IGF1), the ligand of IGF1R, upregulated HOXA13 expression through the PI3K/AKT/HIF1α pathway. Knockdown of HOXA13 decreased IGF1-mediated CRC metastasis. In addition, the combined treatment of ACLY inhibitor ETC-1002 and IGF1R inhibitor Linsitinib dramatically suppressed HOXA13-mediated CRC metastasis. In conclusion, HOXA13 is a prognostic biomarker in CRC patients. Targeting the IGF1-HOXA13-IGF1R positive feedback loop may provide a potential therapeutic strategy for the treatment of HOXA13-driven CRC metastasis.


Assuntos
ATP Citrato (pro-S)-Liase/metabolismo , Neoplasias Colorretais/metabolismo , Proteínas de Homeodomínio/metabolismo , Fator de Crescimento Insulin-Like I/metabolismo , Fatores de Transcrição/metabolismo , ATP Citrato (pro-S)-Liase/antagonistas & inibidores , Idoso , Animais , Linhagem Celular Tumoral , Neoplasias Colorretais/patologia , Ácidos Dicarboxílicos/farmacologia , Ácidos Graxos/farmacologia , Feminino , Células HEK293 , Xenoenxertos , Proteínas de Homeodomínio/antagonistas & inibidores , Humanos , Fator de Crescimento Insulin-Like I/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Pessoa de Meia-Idade , Metástase Neoplásica , Receptor IGF Tipo 1/antagonistas & inibidores , Receptor IGF Tipo 1/metabolismo , Proteínas Recombinantes/farmacologia , Fatores de Transcrição/antagonistas & inibidores , Regulação para Cima
5.
Am J Physiol Endocrinol Metab ; 320(6): E1138-E1147, 2021 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-33938236

RESUMO

Insulin and insulin-like growth factor-1 (IGF-1) are fetal hormones critical to establishing normal fetal growth. Experimentally elevated IGF-1 concentrations during late gestation increase fetal weight but lower fetal plasma insulin concentrations. We therefore hypothesized that infusion of an IGF-1 analog for 1 wk into late gestation fetal sheep would attenuate fetal glucose-stimulated insulin secretion (GSIS) and insulin secretion in islets isolated from these fetuses. Late gestation fetal sheep received infusions with IGF-1 LR3 (IGF-1, n = 8), an analog of IGF-1 with low affinity for the IGF binding proteins and high affinity for the IGF-1 receptor, or vehicle control (CON, n = 9). Fetal GSIS was measured with a hyperglycemic clamp (IGF-1, n = 8; CON, n = 7). Fetal islets were isolated, and insulin secretion was assayed in static incubations (IGF-1, n = 8; CON, n = 7). Plasma insulin and glucose concentrations in IGF-1 fetuses were lower compared with CON (P = 0.0135 and P = 0.0012, respectively). During the GSIS study, IGF-1 fetuses had lower insulin secretion compared with CON (P = 0.0453). In vitro, glucose-stimulated insulin secretion remained lower in islets isolated from IGF-1 fetuses (P = 0.0447). In summary, IGF-1 LR3 infusion for 1 wk into fetal sheep lowers insulin concentrations and reduces fetal GSIS. Impaired insulin secretion persists in isolated fetal islets indicating an intrinsic islet defect in insulin release when exposed to IGF-1 LR3 infusion for 1 wk. We speculate this alteration in the insulin/IGF-1 axis contributes to the long-term reduction in ß-cell function in neonates born with elevated IGF-1 concentrations following pregnancies complicated by diabetes or other conditions associated with fetal overgrowth.NEW & NOTEWORTHY After a 1-wk infusion of IGF-1 LR3, late gestation fetal sheep had lower plasma insulin and glucose concentrations, reduced fetal glucose-stimulated insulin secretion, and decreased fractional insulin secretion from isolated fetal islets without differences in pancreatic insulin content.


Assuntos
Feto/efeitos dos fármacos , Glucose/farmacologia , Secreção de Insulina/efeitos dos fármacos , Fator de Crescimento Insulin-Like I/farmacologia , Ilhotas Pancreáticas/efeitos dos fármacos , Animais , Diabetes Gestacional/metabolismo , Esquema de Medicação , Feminino , Doenças Fetais/metabolismo , Macrossomia Fetal/metabolismo , Macrossomia Fetal/patologia , Feto/metabolismo , Idade Gestacional , Bombas de Infusão , Fator de Crescimento Insulin-Like I/administração & dosagem , Ilhotas Pancreáticas/metabolismo , Pancreatopatias/metabolismo , Gravidez , Ovinos
6.
Int J Mol Sci ; 22(8)2021 Apr 14.
Artigo em Inglês | MEDLINE | ID: mdl-33919940

RESUMO

Deficiency of pregnancy-associated plasma protein-A2 (PAPP-A2), an IGF-1 availability regulator, causes postnatal growth failure and dysregulation of bone size and density. The present study aimed to determine the effects of recombinant murine IGF-1 (rmIGF-1) on bone composition and remodeling in constitutive Pappa2 knock-out (ko/ko) mice. To address this challenge, X-ray diffraction (XRD), attenuated total reflection-fourier transform infra-red (ATR-FTIR) spectroscopy and gene expression analysis of members of the IGF-1 system and bone resorption/formation were performed. Pappa2ko/ko mice (both sexes) had reduced body and bone length. Male Pappa2ko/ko mice had specific alterations in bone composition (mineral-to-matrix ratio, carbonate substitution and mineral crystallinity), but not in bone remodeling. In contrast, decreases in collagen maturity and increases in Igfbp3, osteopontin (resorption) and osteocalcin (formation) characterized the bone of Pappa2ko/ko females. A single rmIGF-1 administration (0.3 mg/kg) induced short-term changes in bone composition in Pappa2ko/ko mice (both sexes). rmIGF-1 treatment in Pappa2ko/ko females also increased collagen maturity, and Igfbp3, Igfbp5, Col1a1 and osteopontin expression. In summary, acute IGF-1 treatment modifies bone composition and local IGF-1 response to bone remodeling in mice with Pappa2 deficiency. These effects depend on sex and provide important insights into potential IGF-1 therapy for growth failure and bone loss and repair.


Assuntos
Reabsorção Óssea/genética , Fator de Crescimento Insulin-Like I/genética , Osteogênese/efeitos dos fármacos , Proteína Plasmática A Associada à Gravidez/genética , Animais , Densidade Óssea/efeitos dos fármacos , Remodelação Óssea/efeitos dos fármacos , Remodelação Óssea/genética , Reabsorção Óssea/tratamento farmacológico , Reabsorção Óssea/patologia , Proteínas de Transporte/genética , Colágeno Tipo I/genética , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Humanos , Proteína 3 de Ligação a Fator de Crescimento Semelhante à Insulina/genética , Fator de Crescimento Insulin-Like I/farmacologia , Camundongos , Camundongos Knockout , Osteocalcina/genética , Osteopontina/genética , Caracteres Sexuais
7.
Neurosci Lett ; 751: 135809, 2021 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-33713748

RESUMO

Migraineurs experience increased oxidative stress which drives the initiation and maintenance of migraine-related pain in animal models and, by extension, migraine in humans. Oxidative stress augments calcitonin gene-related peptide (CGRP) levels, a mediator of migraine pain. Insulin-like growth factor-1 (IGF-1), a neuroprotective growth factor, reduces susceptibility to spreading depression, a preclinical model of migraine, in cultured brain slices by blocking oxidative stress and neuroinflammation from microglia. Similarly, nasal delivery of IGF-1 inhibits spreading depression in vivo. After recurrent cortical spreading depression, nasal administration of IGF-1 also significantly reduces trigeminal ganglion oxidative stress and CGRP levels as well as trigeminocervical c-Fos activation. Here, we probed for the impact of nasal IGF-1 pretreatment on trigeminal system activation using a second well-established preclinical model of migraine, systemic nitroglycerin injection. Adult male rats were treated with one of three doses of IGF-1 (37.5, 75 or 150 µg) and the optimal dose found in males was subsequently used for treatment of female rats. One day later, animals received an intraperitoneal injection of nitroglycerin. Measurements taken two hours later after nitroglycerin alone showed increased surrogate markers of trigeminal activation - oxidative stress and CGRP in the trigeminal ganglion and c-Fos in the trigeminocervical complex compared to vehicle control. These effects were significantly reduced at all doses of IGF-1 for trigeminal ganglion metrics of oxidative stress and CGRP and only at the lowest dose in both males and females for c-Fos. The latter inverted U-shaped or hormetic response is seen in enzyme-targeting drugs. While the specific mechanisms remain to be explored, our data here supports the ability of IGF-1 to preserve mitochondrial and antioxidant pathway homeostasis as means to prevent nociceptive activation in the trigeminal system produced by an experimental migraine model.


Assuntos
Peptídeo Relacionado com Gene de Calcitonina/metabolismo , Fator de Crescimento Insulin-Like I/farmacologia , Transtornos de Enxaqueca/tratamento farmacológico , Nitroglicerina/farmacologia , Estresse Oxidativo , Gânglio Trigeminal/metabolismo , Administração Intranasal , Animais , Feminino , Fator de Crescimento Insulin-Like I/administração & dosagem , Fator de Crescimento Insulin-Like I/uso terapêutico , Masculino , Transtornos de Enxaqueca/etiologia , Transtornos de Enxaqueca/metabolismo , Proteínas Proto-Oncogênicas c-fos/metabolismo , Ratos , Ratos Wistar , Gânglio Trigeminal/efeitos dos fármacos , Gânglio Trigeminal/fisiologia
8.
Int J Mol Sci ; 22(5)2021 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-33671044

RESUMO

Anti-Müllerian hormone (AMH) is secreted by Sertoli or granulosa cells. Recent evidence suggests that AMH may play a role in the pathogenesis of hypogonadotropic hypogonadism (HH) and that its serum levels could help to discriminate HH from delayed puberty. Moreover, the growth hormone (GH)/insulin-like growth factor 1 (IGF1) system may be involved in the function of gonadotropin-releasing hormone (GnRH) neurons, as delayed puberty is commonly found in patients with GH deficiency (GHD) or with Laron syndrome, a genetic form of GH resistance. The comprehension of the stimuli enhancing the migration and secretory activity of GnRH neurons might shed light on the causes of delay of puberty or HH. With these premises, we aimed to better clarify the role of the AMH, GH, and IGF1 on GnRH neuron migration and GnRH secretion, by taking advantage of previously established models of immature (GN11 cell line) and mature (GT1-7 cell line) GnRH neurons. Expression of Amhr, Ghr, and Igf1r genes was confirmed in both cell lines. Cells were then incubated with increasing concentrations of AMH (1.5-150 ng/mL), GH (3-1000 ng/mL), or IGF1 (1.5-150 ng/mL). All hormones were able to support GN11 cell chemomigration. AMH, GH, and IGF1 significantly stimulated GnRH secretion by GT1-7 cells after a 90-min incubation. To the best of our knowledge, this is the first study investigating the direct effects of GH and IGF1 in GnRH neuron migration and of GH in the GnRH secreting pattern. Taken together with previous basic and clinical studies, these findings may provide explanatory mechanisms for data, suggesting that AMH and the GH-IGF1 system play a role in HH or the onset of puberty.


Assuntos
Hormônio Antimülleriano/farmacologia , Hormônio Liberador de Gonadotropina/metabolismo , Hormônio do Crescimento Humano/farmacologia , Fator de Crescimento Insulin-Like I/farmacologia , Neurônios/fisiologia , Animais , Movimento Celular , Células Cultivadas , Camundongos , Neurônios/citologia , Neurônios/efeitos dos fármacos
9.
PLoS One ; 16(2): e0243727, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33534866

RESUMO

In vitro embryo production systems are limited by their inability to consistently produce embryos with the competency to develop to the blastocyst stage, survive cryopreservation, and establish a pregnancy. Previous work identified a combination of three cytokines [fibroblast growth factor 2 (FGF2), leukemia inhibitory factor (LIF), and insulin-like growth factor 1 (IGF1)], called FLI, that we hypothesize improve preimplantation development of bovine embryos in vitro. To test this hypothesis, FLI was supplemented into oocyte maturation or embryo culture medium. Embryos were produced in vitro using abattoir-derived oocytes and fertilized with sperm from a single bull known to have high fertility. After an 18-20 h fertilization period, putative zygotes were cultured in synthetic oviductal fluid (SOF) for 8 days. The addition of FLI to the oocyte maturation medium increased (P < 0.05) the dissociation of transzonal projections at 12, 18, and 24 h of maturation, as well as, the proportion of oocytes that reached the metaphase II stage of meiosis. Additionally, lipid content was decreased (P < 0.05) in the blastocyst stage embryo. The addition of FLI during the culture period increased development to the blastocyst stage, cytoskeleton integrity, and survival following slow freezing, as well as, decreased post thaw cell apoptosis (P < 0.05). In conclusion, the supplementation of these cytokines in vitro has the potential to alleviate some of the challenges associated with the cryo-survival of in vitro produced bovine embryos through improving embryo development and embryo quality.


Assuntos
Bovinos/embriologia , Criopreservação/veterinária , Embrião de Mamíferos/embriologia , Fator 2 de Crescimento de Fibroblastos , Fator de Crescimento Insulin-Like I , Fator Inibidor de Leucemia , Animais , Blastocisto/citologia , Blastocisto/efeitos dos fármacos , Blastocisto/ultraestrutura , Criopreservação/métodos , Embrião de Mamíferos/efeitos dos fármacos , Embrião de Mamíferos/ultraestrutura , Feminino , Fertilização In Vitro/métodos , Fertilização In Vitro/veterinária , Fator 2 de Crescimento de Fibroblastos/administração & dosagem , Fator 2 de Crescimento de Fibroblastos/farmacologia , Técnicas de Maturação in Vitro de Oócitos/métodos , Técnicas de Maturação in Vitro de Oócitos/veterinária , Fator de Crescimento Insulin-Like I/administração & dosagem , Fator de Crescimento Insulin-Like I/farmacologia , Fator Inibidor de Leucemia/administração & dosagem , Fator Inibidor de Leucemia/farmacologia , Gravidez
10.
Sci Rep ; 11(1): 457, 2021 01 11.
Artigo em Inglês | MEDLINE | ID: mdl-33432124

RESUMO

Electrospun fibrous scaffolds combined with bioactive factors can display impressive performance as an ideal wound dressing, since they can mimic the composition and physicochemical properties of the extracellular matrix (ECM). The aim of this study was to fabricate a new composite biomaterial (IGF1-DA and Os-DA-modified PLGA electrospun fibrous scaffold) for wound healing, using a rat model for experimental evaluation. A small pentapeptide tag composed of DA-Lys-DA-Lys-DA residues was introduced into insulin-like growth factor 1 (IGF1) and the antimicrobial peptide Os to prepare IGF1 and Os modified with 3,4-dihydroxyphenylalanine (DA) (IGF1-DA and Os-DA). The designed chimeric growth factor and antimicrobial peptide could successfully anchor to PLGA electrospun fibrous scaffolds, and the growth factor and antimicrobial peptide could be controllably released from the electrospun fibrous scaffolds. The results showed that the IGF1-DA and Os-DA-modified PLGA electrospun fibrous scaffolds (PLGA/Os-DA/IGF1-DA) exhibited high hydrophilicity and antimicrobial activity; moreover, the porous network of the scaffolds was similar to that of the natural ECM, which can provide a favourable environment for BALB/C 3T3 cells growth. The in vivo application of PLGA/Os-DA/IGF1-DA electrospun fibrous scaffolds in rat skin wounds resulted in improved wound recovery and tissue regeneration rate. The experimental results indicated that the IGF1-DA and Os-DA could effectively bind to PLGA electrospun fibrous scaffolds, promote wound healing and prevent infection in rats, thereby suggesting that PLGA/Os-DA/IGF1-DA electrospun fibrous scaffolds have a wide application value in the field of skin wound repair.


Assuntos
Bandagens , Fator de Crescimento Insulin-Like I , Copolímero de Ácido Poliláctico e Ácido Poliglicólico , Pele/lesões , Tecidos Suporte , Cicatrização , Animais , Células 3T3 BALB , Fenômenos Químicos , Modelos Animais de Doenças , Matriz Extracelular , Fator de Crescimento Insulin-Like I/farmacologia , Camundongos , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/farmacologia , Ratos , Regeneração/efeitos dos fármacos , Dermatopatias Bacterianas/prevenção & controle , Fenômenos Fisiológicos da Pele , Tecidos Suporte/química , Cicatrização/efeitos dos fármacos
11.
Am J Physiol Endocrinol Metab ; 320(3): E527-E538, 2021 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-33427051

RESUMO

Insulin-like growth factor-1 (IGF-1) is an important fetal growth factor. However, the role of fetal IGF-1 in increasing placental blood flow, nutrient transfer, and nutrient availability to support fetal growth and protein accretion is not well understood. Catheterized fetuses from late gestation pregnant sheep received an intravenous infusion of LR3 IGF-1 (LR3 IGF-1; n = 8) or saline (SAL; n = 8) for 1 wk. Sheep then underwent a metabolic study to measure uterine and umbilical blood flow, nutrient uptake rates, and fetal protein kinetic rates. By the end of the infusion, fetal weights were not statistically different between groups (SAL: 3.260 ± 0.211 kg, LR3 IGF-1: 3.682 ± 0.183; P = 0.15). Fetal heart, adrenal gland, and spleen weights were higher (P < 0.05), and insulin was lower in LR3 IGF-1 (P < 0.05). Uterine and umbilical blood flow and umbilical uptake rates of glucose, lactate, and oxygen were similar between groups. Umbilical amino acid uptake rates were lower in LR3 IGF-1 (P < 0.05) as were fetal concentrations of multiple amino acids. Fetal protein kinetic rates were similar. LR3 IGF-1 skeletal muscle had higher myoblast proliferation (P < 0.05). In summary, LR3 IGF-1 infusion for 1 wk into late gestation fetal sheep increased the weight of some fetal organs. However, because umbilical amino acid uptake rates and fetal plasma amino acid concentrations were lower in the LR3 IGF-1 group, we speculate that animals treated with LR3 IGF-1 can efficiently utilize available nutrients to support organ-specific growth in the fetus rather than by stimulating placental blood flow or nutrient transfer to the fetus.NEW & NOTEWORTHY After a 1-wk infusion of LR3 IGF-1, late gestation fetal sheep had lower umbilical uptake rates of amino acids, lower fetal arterial amino acid and insulin concentrations, and lower fetal oxygen content; however, LR-3 IGF-1-treated fetuses were still able to effectively utilize the available nutrients and oxygen to support organ growth and myoblast proliferation.


Assuntos
Desenvolvimento Fetal/efeitos dos fármacos , Fator de Crescimento Insulin-Like I/farmacologia , Nutrientes/metabolismo , Animais , Metabolismo Energético/efeitos dos fármacos , Feminino , Sangue Fetal/metabolismo , Peso Fetal/efeitos dos fármacos , Feto/efeitos dos fármacos , Feto/metabolismo , Fator de Crescimento Insulin-Like I/administração & dosagem , Masculino , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/embriologia , Músculo Esquelético/crescimento & desenvolvimento , Músculo Esquelético/metabolismo , Tamanho do Órgão/efeitos dos fármacos , Placenta/efeitos dos fármacos , Placentação/efeitos dos fármacos , Gravidez , Ovinos
12.
Mol Cell Endocrinol ; 519: 111053, 2021 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-33035625

RESUMO

Insulin-like growth factor-1 (IGF-1) is a potent neuroprotective polypeptide that exerts neuroprotective effects via the IGF-1 receptor (IGF-1R). Our previous study reported that G protein-coupled estrogen receptor (GPER) was involved in the anti-apoptotic effect of IGF-1. The present study was designed to investigate the anti-inflammatory effect of IGF-1 in association with astrocyte activation and the molecular details of the interaction between IGF-1R and GPER. We showed that IGF-1 could improve 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced motor deficits and attenuate the upregulation of cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) both in vivo and in vitro. The IGF-1R antagonist JB-1 and the GPER antagonist G15 could antagonize the anti-inflammatory effect of IGF-1. Silencing GPER abrogated the inhibitory effect of IGF-1 on 1-methyl-4-phenylpyridinium (MPP+)-induced upregulation of COX-2 and iNOS in primary astrocytes. Moreover, the MPP + -induced inflammatory response was related to the activation of mitogen-activated protein kinases (MAPKs) and NF-κB signaling pathways. The inhibitory effects of IGF-1 on the phosphorylation of p38, JNK and IκB could be blocked by JB-1. G15 antagonized the inhibitory effects of IGF-1 on p-JNK and p-IκB, but not p-p38. Furthermore, IGF-1 treatment alone increased the expression of GPER, which was blocked by JB-1, the phosphatidylinositol 3-kinase (PI3-K) antagonist LY294002 and the MEK antagonist PD98059 in primary astrocytes. Overall, we show for the first time that GPER may contribute to the anti-inflammatory effect of IGF-1 against MPTP/MPP + -induced astrocyte activation. IGF-1 could regulate the expression of GPER via the IGF-1R/PI3-K/MAPK signaling pathway in primary astrocytes.


Assuntos
1-Metil-4-fenilpiridínio/toxicidade , Anti-Inflamatórios/farmacologia , Astrócitos/metabolismo , Fator de Crescimento Insulin-Like I/farmacologia , Receptor IGF Tipo 1/metabolismo , Receptores de Estrogênio/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , 1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina , Animais , Astrócitos/efeitos dos fármacos , Comportamento Animal , Benzodioxóis/farmacologia , Células Cultivadas , Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/metabolismo , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Camundongos Endogâmicos C57BL , NF-kappa B/metabolismo , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico Sintase Tipo II/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Fosforilação/efeitos dos fármacos , Quinolinas/farmacologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Substância Negra/metabolismo , Regulação para Cima/efeitos dos fármacos
13.
Sci Rep ; 10(1): 21583, 2020 12 09.
Artigo em Inglês | MEDLINE | ID: mdl-33299022

RESUMO

The scarcity of chondrocytes is a major challenge for cartilage tissue engineering. Monolayer expansion is necessary to amplify the limited number of chondrocytes needed for clinical application. Growth factors are often added to improve monolayer culture conditions, promoting proliferation, and enhancing chondrogenesis. Limited knowledge on the biosafety of the cell products manipulated with growth factors in culture has driven this study to evaluate the impact of growth factor cocktail supplements in chondrocyte culture medium on chondrocyte genetic stability and tumorigenicity. The growth factors were basic fibroblast growth factor (b-FGF), transforming growth factor ß2 (TGF ß2), insulin-like growth factor 1 (IGF-1), insulin-transferrin-selenium (ITS), and platelet-derived growth factor (PD-GF). Nasal septal chondrocytes cultured in growth factor cocktail exhibited a significantly high proliferative capacity. Comet assay revealed no significant DNA damage. Flow cytometry showed chondrocytes were mostly at G0-G1 phase, exhibiting normal cell cycle profile with no aneuploidy. We observed a decreased tumour suppressor genes' expression (p53, p21, pRB) and no TP53 mutations or tumour formation after 6 months of implantation in nude mice. Our data suggest growth factor cocktail has a low risk of inducing genotoxic and tumorigenic effects on chondrocytes up to passage 6 with 16.6 population doublings. This preclinical tumorigenicity and genetic instability evaluation is crucial for further clinical works.


Assuntos
Proliferação de Células/efeitos dos fármacos , Condrócitos/citologia , Condrogênese/efeitos dos fármacos , Meios de Cultura/farmacologia , Engenharia Tecidual/métodos , Animais , Ciclo Celular/efeitos dos fármacos , Forma Celular/efeitos dos fármacos , Condrócitos/efeitos dos fármacos , Dano ao DNA/efeitos dos fármacos , Fator 2 de Crescimento de Fibroblastos/farmacologia , Humanos , Fator de Crescimento Insulin-Like I/farmacologia , Camundongos , Camundongos Nus , Fator de Crescimento Derivado de Plaquetas , Fator de Crescimento Transformador beta2/farmacologia
14.
Bratisl Lek Listy ; 121(12): 853-857, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33300353

RESUMO

OBJECTIVES: The objective of this study was to evaluate the effect of IGF1 and FGF2 growth factors on the differentiation of human adipose tissue­derived mesenchymal stem cells (MSCs) into skeletal muscle cells. METHODS: MSCs were divided into four groups. Group I (control group) was incubated only in myogenic medium, group II was incubated by adding 100 ng/ml FGF2 to the myogenic medium, group III was incubated by adding 20 ng/ml IGF1 to the myogenic medium, group IV was incubated by adding 100 ng/ml FGF2 and 20 ng/ml IGF1 to the myogenic medium. Cells dyed with MyoD1 antibodies were analyzed by flow cytometry so as to determine the myogenic differentiation on day 28. RESULTS: It was confirmed that 11.5 % of the control group, 39.2 % of the FGF2 group, 23.1 % of the IGF1 group, and 39.3 % of the IGF1-FGF2 group showed differentiation. CONCLUSION: Our results show that IGF1 and FGF2 have a positive contribution to myogenic differentiation of MSCs. They contribute to the studies related to muscle diseases and their treatment by the fact that growth factors support the feature of regeneration capacity and differentiation (Tab. 2, Fig. 7, Ref. 23).


Assuntos
Diferenciação Celular , Fator 2 de Crescimento de Fibroblastos/farmacologia , Fator de Crescimento Insulin-Like I/farmacologia , Células-Tronco Mesenquimais/citologia , Células Musculares/citologia , Músculo Esquelético/citologia , Células Cultivadas , Humanos
15.
Int J Mol Sci ; 22(1)2020 Dec 28.
Artigo em Inglês | MEDLINE | ID: mdl-33379239

RESUMO

Encephalopathy of Prematurity (EoP) is a major cause of morbidity in (extreme) preterm neonates. Though the majority of EoP research has focused on failure of oligodendrocyte maturation as an underlying pathophysiological mechanism, recent pioneer work has identified developmental disturbances in inhibitory interneurons to contribute to EoP. Here we investigated interneuron abnormalities in two experimental models of EoP and explored the potential of two promising treatment strategies, namely intranasal mesenchymal stem cells (MSCs) or insulin-like growth factor I (IGF1), to restore interneuron development. In rats, fetal inflammation and postnatal hypoxia led to a transient increase in total cortical interneuron numbers, with a layer-specific deficit in parvalbumin (PV)+ interneurons. Additionally, a transient excess of total cortical cell density was observed, including excitatory neuron numbers. In the hippocampal cornu ammonis (CA) 1 region, long-term deficits in total interneuron numbers and PV+ subtype were observed. In mice subjected to postnatal hypoxia/ischemia and systemic inflammation, total numbers of cortical interneurons remained unaffected; however, subtype analysis revealed a global, transient reduction in PV+ cells and a long-lasting layer-specific increase in vasoactive intestinal polypeptide (VIP)+ cells. In the dentate gyrus, a long-lasting deficit of somatostatin (SST)+ cells was observed. Both intranasal MSC and IGF1 therapy restored the majority of interneuron abnormalities in EoP mice. In line with the histological findings, EoP mice displayed impaired social behavior, which was partly restored by the therapies. In conclusion, induction of experimental EoP is associated with model-specific disturbances in interneuron development. In addition, intranasal MSCs and IGF1 are promising therapeutic strategies to aid interneuron development after EoP.


Assuntos
Córtex Cerebral/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Hipóxia-Isquemia Encefálica/terapia , Fator de Crescimento Insulin-Like I/uso terapêutico , Interneurônios , Transplante de Células-Tronco Mesenquimais , Administração Intranasal , Animais , Córtex Cerebral/patologia , Modelos Animais de Doenças , Feminino , Neurônios GABAérgicos , Hipocampo/patologia , Hipóxia-Isquemia Encefálica/patologia , Fator de Crescimento Insulin-Like I/farmacologia , Camundongos Endogâmicos C57BL , Gravidez , Ratos Wistar , Comportamento Social
16.
Biosci Biotechnol Biochem ; 84(12): 2428-2439, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32862787

RESUMO

Resveratrol is a natural polyphenol with beneficial antioxidant properties. It suppresses the migration of osteoblast-like MC3T3-E1 cells induced by epidermal growth factor, via SIRT1-mediated inhibition of SAPK/JNK and Akt. Moreover, insulin-like growth factor-I (IGF-I) stimulates the migration involving the pathways of p44/p42 mitogen-activated protein (MAP) kinase and Akt. Therefore, we investigated the effects of resveratrol on IGF-I-induced cell migration. Resveratrol and SRT1720, an activator of SIRT1, suppressed IGF-I-induced migration. Inauhzin, a SIRT1 inhibitor, significantly rescued the inhibition of IGF-I-induced cell migration by resveratrol. Resveratrol inhibited IGF-I-induced phosphorylation of p44/p42 MAP kinase but not Akt. SRT1720 inhibited IGF-I-induced phosphorylation of p44/p42 MAP kinase. Furthermore, PD98059, p44/p42 MAP kinase inhibitor, alone suppressed IGF-I-induced osteoblast migration, but did not affect the suppressive effect of resveratrol when administered concomitantly. These findings strongly suggest that resveratrol suppresses IGF-I-induced osteoblast migration via SIRT1 activation at least partially by attenuating the p44/p42 MAP kinase pathway.


Assuntos
Fator de Crescimento Insulin-Like I/farmacologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Osteoblastos/citologia , Osteoblastos/efeitos dos fármacos , Resveratrol/farmacologia , Células 3T3 , Animais , Ativação Enzimática/efeitos dos fármacos , Camundongos , Osteoblastos/metabolismo , Fosforilação/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Sirtuína 1/metabolismo
17.
Am J Physiol Endocrinol Metab ; 319(4): E734-E743, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-32865008

RESUMO

Autophagy dysfunctions are involved in the pathogenesis of Parkinson's disease (PD). In the present study, we aimed to evaluate the involvement of G protein-coupled estrogen receptor (GPER) in the inhibitory effect of insulin-like growth factor-1 (IGF-1) against excessive autophagy in PD animal and cellular models. 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) treatment significantly induced mouse movement disorder and decreased the protein level of tyrosine hydroxylase (TH) in the substantia nigra (SN) and dopamine (DA) content in striatum. Along with the dopamine neuron injury, we observed significant upregulations of microtubule-associated light chain-3 II (LC3-II) and α-synuclein as well as a downregulation of P62 in MPTP-treated mice. These changes could be restored by IGF-1 pretreatment. Cotreatment with IGF-1R antagonist JB-1 or GPER antagonist G15 could block the neuroprotective effects of IGF-1. 1-Methy-4-phenylpyridinium (MPP+) treatment could also excessively activate autophagy along with the reduction of cell viability in SH-SY5Y cells. IGF-1 could inhibit the neurotoxicity through promoting the phosphorylation of Akt and mammalian target of rapamycin (mTOR), which could also be antagonized by JB-1 or G15. These data suggest that IGF-1 inhibits MPTP/MPP+-induced autophagy on dopaminergic neurons through the IGF-1R/PI3K-Akt-mTOR pathway and GPER.


Assuntos
Autofagia/efeitos dos fármacos , Neurônios Dopaminérgicos/efeitos dos fármacos , Fator de Crescimento Insulin-Like I/farmacologia , Intoxicação por MPTP/prevenção & controle , Receptores de Estrogênio/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Transdução de Sinais/efeitos dos fármacos , Animais , Humanos , Intoxicação por MPTP/psicologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neostriado/efeitos dos fármacos , Neostriado/metabolismo , Proteína Oncogênica v-akt/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Equilíbrio Postural/efeitos dos fármacos , Receptor IGF Tipo 1 , Serina-Treonina Quinases TOR/metabolismo
18.
Int J Mol Sci ; 21(18)2020 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-32899449

RESUMO

(1) Background: Activation of the PI3K-AKT pathway controls most hallmarks of cancer, and the hedgehog (HH) pathway has been associated with oral squamous cell carcinoma (OSCC) development and progression. We hypothesized that fibroblast-derived insulin-like growth factor-1 (IGF-1) acts in oral squamous cell carcinoma (OSCC) cells, leading to the non-canonical activation of the HH pathway, maintaining AKT activity and promoting tumor aggressiveness. (2) Methods: Primary fibroblasts (MF1) were genetically engineered for IGF-1 overexpression (MF1-IGF1) and CRISPR/Cas9-mediated IGF1R silencing was performed in SCC-4 cells. SCC-4 cells were co-cultured with fibroblasts or incubated with fibroblast conditioned medium (CM) or rIGF-1 for functional assays and the evaluation of AKT and HH pathways. (3) Results: Gene expression analysis confirmed IGF-1 overexpression in MF1-IGF1 and the absence of IGF-1 expression in SCC-4, while elevated IGF1R expression was detected. IGF1R silencing was associated with decreased survival of SCC-4 cells. Ihh was expressed in both MF1 and MF1-IGF1, and increased levels of GLI1 mRNA were observed in SCC-4 after stimulation with CM-MF1. Activation of both PI3K-AKT and the HH pathway (GLI1, Ihh and SMO) were identified in SCC-4 cells cultured in the presence of MF1-IGF1-CM. rIGF-1 promoted tumor cell proliferation, migration, invasion and tumorsphere formation, whereas CM-MF1 significantly stimulated angiogenesis. (4) Conclusions: IGF-1 exerts pro-tumorigenic effects by stimulating SCC-4 cell proliferation, migration, invasion and stemness. AKT and HH pathways were activated by IGF-1 in SCC-4, reinforcing its influence on the regulation of these signaling pathways.


Assuntos
Proteínas Hedgehog/metabolismo , Fator de Crescimento Insulin-Like I/farmacologia , Neoplasias Bucais/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço/metabolismo , Carcinoma de Células Escamosas/patologia , Técnicas de Cultura de Células , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Fator de Crescimento Insulin-Like I/metabolismo , Masculino , Neoplasias Bucais/tratamento farmacológico , Neoplasias Bucais/patologia , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Neovascularização Patológica/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Transdução de Sinais/efeitos dos fármacos , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia
19.
Oxid Med Cell Longev ; 2020: 5173184, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32849999

RESUMO

Glutamate-induced neurotoxicity is involved in various neuronal diseases, such as Alzheimer's disease. We have previously reported that glutamate attenuated the survival signaling of insulin-like growth factor-1 (IGF-1) by N-methyl-D-aspartate receptors (NMDARs) in cultured cortical neurons, which is viewed as a novel mechanism of glutamate-induced neurotoxicity. However, the phosphorylation sites of IGF-1 receptor (IGF-1R) affected by glutamate remain to be elucidated, and importantly, which subtype of NMDARs plays a major role in attenuating the prosurvival effect of IGF-1 is still unknown. In the present study, glutamate was found to attenuate the tyrosine phosphorylation of the IGF-1R and the prosurvival effect of IGF-1 in primary cultured cortical neurons. NMDAR inhibitors, MK801 and AP-5, blocked the inhibitory effect of glutamate on the phosphorylation of IGF-1R and increased cell survival, while DNQX, LY341495, and CPCCOEt had no effect. Interestingly, we found that glutamate decreased the phosphorylation of tyrosine residues 1131, 1135/1136, 1250/1251, and 1316, while it had no effect on tyrosine 950 in cortical neurons. Moreover, using specific antagonists and siRNA to downregulate individual NMDAR subunits, we found that the activation of NR2B-containing NMDARs was essential for glutamate to inhibit IGF-1 signaling. These findings indicate that the glutamate-induced attenuation of IGF-1 signaling is mediated by NR2B-containing NMDARs. Our study also proposes a novel mechanism of altering neurotrophic factor signaling by the activation of NMDARs.


Assuntos
Córtex Cerebral/patologia , Ácido Glutâmico/toxicidade , Neurônios/patologia , Receptor IGF Tipo 1/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Animais , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Feminino , Humanos , Fator de Crescimento Insulin-Like I/farmacologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Camundongos , Modelos Biológicos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Fosforilação/efeitos dos fármacos , Fosfotirosina/metabolismo , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores
20.
Anim Sci J ; 91(1): e13422, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32648312

RESUMO

The aim of this study was to identify factors that regulate ruminal epithelial insulin-like growth factor-binding protein (IGFBP) expression and determine its role in rumen epithelial cell proliferation. Primary bovine rumen epithelial cells (BREC) were incubated with short-chain fatty acids (SCFAs) at pH 7.4 or 5.6, lactate, lipopolysaccharide (LPS), insulin-like growth factor-I (IGF-I), -II (IGF-II), or recombinant bovine IGFBP2 (rbIGFBP2). The mRNA expression levels of IGFBP in BREC were analyzed using quantitative real-time polymerase chain reaction (qRT-PCR). The proliferation rate of BREC was analyzed using a WST-1 assay. IGFBP2 gene expression tended to be lower with SCFA treatment (p < .1), and IGFBP6 gene expression was significantly lower with SCFA treatment (p < .05). IGFBP3 and IGFBP6 gene expression tended to be higher with d-Lactate treatment (p < .1). IGFBP3 gene expression was significantly higher (p < .05) with LPS treatment. BREC treated with IGF-I grew more rapidly than vehicle control-treated cells (p < .01); however, recombinant bovine rbIGFBP2 inhibited IGF-I-induced proliferation. IGF-II and/or rbIGFBP2 did not affect BREC proliferation. Taken together, SCFA treatment decreased IGFBP2 and IGFBP6 expression in rumen epithelial cells, and lower expression of these IGFBP might promote rumen epithelial cell proliferation by facilitating IGF-I.


Assuntos
Proliferação de Células/genética , Células Epiteliais/fisiologia , Regulação da Expressão Gênica no Desenvolvimento/genética , Expressão Gênica/genética , Proteína 2 de Ligação a Fator de Crescimento Semelhante à Insulina/genética , Proteína 2 de Ligação a Fator de Crescimento Semelhante à Insulina/metabolismo , Proteína 3 de Ligação a Fator de Crescimento Semelhante à Insulina/genética , Proteína 3 de Ligação a Fator de Crescimento Semelhante à Insulina/metabolismo , Proteína 6 de Ligação a Fator de Crescimento Semelhante à Insulina/genética , Proteína 6 de Ligação a Fator de Crescimento Semelhante à Insulina/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Rúmen/citologia , Animais , Bovinos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Ácidos Graxos Voláteis/farmacologia , Expressão Gênica/efeitos dos fármacos , Concentração de Íons de Hidrogênio , Fator de Crescimento Insulin-Like I/metabolismo , Fator de Crescimento Insulin-Like I/farmacologia
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