Decreased Expression Of Insulin-like Growth Factor 1 Research Articles

Insulin-Like Growth Factor-1 Enhances Motoneuron Survival and Inhibits Neuroinflammation After Spinal Cord Transection in Zebrafish.

Insulin-like growth factor-1 (IGF-1) is a neurotrophic factor produced locally in the central nervous system which can promote axonal regeneration, protect motoneurons, and inhibit neuroinflammation. In this study, we used the zebrafish spinal transection model to investigate whether IGF-1 plays an important role in the recovery of motor function. Unlike mammals, zebrafish can regenerate axons and restore mobility in remarkably short period after spinal cord transection. Quantitative real-time PCR and immunofluorescence showed decreased IGF-1 expression in the lesion site. Double immunostaining for IGF-1 and Islet-1 (motoneuron marker)/GFAP (astrocyte marker)/Iba-1 (microglia marker) showed that IGF-1 was mainly expressed in motoneurons and was surrounded by astrocyte and microglia. Following administration of IGF-1 morpholino at the lesion site of spinal-transected zebrafish, swimming test showed retarded recovery of mobility, the number of motoneurons was reduced, and increased immunofluorescence density of microglia was caused. Our data suggested that IGF-1 enhances motoneuron survival and inhibits neuroinflammation after spinal cord transection in zebrafish, which suggested that IGF-1 might be involved in the motor recovery.

TGFβ1 Suppresses Neuronal IGF1 via a Let-7F-Dependent Mechanism During Azoxymethane-Induced Hepatic Encephalopathy in Mice

Background and Aim: Hepatic encephalopathy (HE) is a neurological complication that arises after a loss of liver function. HE is associated with increased cerebral edema, neuroinflammation and the onset of cognitive decline. We have previously shown that there is increased expression and secretion of transforming growth factor β1 (TGFβ1) from hepatocytes during the azoxymethane (AOM) model of acute liver failure and HE. Increased circulating TGFβ1 was shown to promote blood-brain barrier permeability and also led to progressive neurological complications via increased activation of its receptor TGFβR2. Insulin-like growth factor 1 (IGF1) is a neuroprotective peptide that can be suppressed by TGFβ1 signaling in other organs. IGF1 expression is regulated by a number of microRNAs, including Let-7f, which is positively regulated by TGFβ1. Therefore, we hypothesize that circulating hepatic-derived TGFβ1 suppresses neural IGF1 via a mechanism involving Let-7f during HE, which subsequently exacerbates neurological decline. Methods: In order to determine the exact contribution of TGFβ1 liver-brain axis signaling in this model, male C57Bl/6 (WT) mice, hepatocyte-specific TGFβ1 knockout mice (floxed TGFβ1 × albumin-Cre) or neuron-specific TGFβR2 knockout mice (floxed TGFβR2 × Thy1-Cre) were injected with the hepatotoxin azoxymethane (AOM). In parallel, WT mice were treated with an anti-TGFβ neutralizing antibody 1 h prior to AOM, or were infused with rIGF1 into the lateral ventricle for 3 days prior to AOM injection. Cognitive impairment was monitored and livers, serum and whole brains were collected at coma. IGF1, TGFβ1, Let-7f and proinflammatory cytokine expression were assessed by immunoblotting, immunohistochemistry and/or qPCR. Microglia were stained by IBA1 and cortex field staining and cell morphology were assessed. In vitro, mouse neurons were transfected with a specific Let-7f inhibitor prior to treatment with rTGFβ1 and the expression of Let-7f, IGF1 and CCL2 were measured. Results: Mice injected with AOM had increased Let-7f and suppressed cortical IGF1 expression. Strategies to inhibit TGFβ1 signaling in the brain (ie hepatocyte-specific TGFβ1 knockout, neuron-specific TGFβR2 knockout or pretreatment with TGFβ neutralizing antibody) attenuated the (i) induction of Let-7f expression, (ii) suppression of cortical IGF1, (iii) neuroinflammation and (iv) neurological decline when compared to WT mice treated with AOM alone. In vitro, treatment of neurons with rTGFβ1 increased the expression of Let-7f and reduced the expression of IGF1 in a Let-7f-dependent manner, while also inducing CCL2 expression. Lastly, rIGF1 infusion in the brain delayed AOM-induced neurological decline and reduced neuroinflammation. Conclusion: Elevated TGFβ1 signaling during HE leads to increased cortical Let-7f expression, decreased IGF1 expression and worse outcomes in AOM-treated mice. These deleterious effects can be reversed by inhibiting neuronal TGFβ1 signaling or by increasing IGF1 concentrations in the brain, indicating that elevated TGFβ1 and suppressed IGF1 contribute to the progression of HE. The authors have none to declare.

Effects of high-fat feeding on growth and expression of IGF-1 and IRS-1 in adolescent rats

Objective To observe the effects of high-fat feeding on growth and the expression of insulin-like growth factor 1(IGF-1), insulin receptor substrate 1(IRS-1) in adolescent rats' liver with non-alcoholic fatty liver disease, and to elucidate the relationship between growth failure in adolescent rats with non-alcoholic fatty liver disease and IGF-1, IRS-1 turbulence. Methods Thirty-six Sprague-Dawley (SD) young rats of 21 days were randomly divided into normal control group(NC group, n=18) and high-fat feeding group(HF group, n=18). Non-alcoholic fatty liver disease(NAFLD) model was induced by feeding the SD rats with high-fat food.Immunohistochemistry was applied to detect the expression levels of IGF-1 and IRS-1 in liver tissue.The expressions of mRNA of IGF-1 and IRS-1 were measured by RT-PCR. Results Compared with NC group, the serum alanine amino transferase(ALT), total cholesterol(TC), triglyceride(TG) of HF group in the 6th, 8th, 12th week were gradually increased.The serum ALT[(194.67±11.15)U/L], TC[(1.81±0.09)mmol/L], TG[(0.34±0.05)mmol/L]contents of HF group at 8th week were higher than those at 6th week[(166.00±22.01)U/L, (1.52±0.22)mmol/L, (0.41±0.12)mmol/L, respectively], and the serum ALT[(213.0±27.67)U/L], TC[(2.15±0.37)mmol/L], TG[(0.38±0.15)mmol/L]contents of the 12th week were significantly increased compared with 6th week and 8th week.The constitution and body length of the HF group were lower than those of the normal control group.With time extended, the liver tissue steatosis, inflammation, the balloon like change of the liver tissue pathology of HF group in 6, 8, 12th week gradually increased.Immunohistochemistry results showed that HF group IRS-1[(1.46±0.23), (0.74±0.17), (0.85±0.31)], IGF-1[(0.92±0.02), (0.83±0.02), (0.77±0.03)]expression gradually decreased, the difference was statistically significant(F=36.024, P<0.05). IGF-1 and IRS-1 mRNA expressions in HF group were consistent. Conclusion The liver tissue IGF-1 and IRS-1 are correlated with the weight and body length.The growth failure of young rats induced by high-fat feeding may be related to the decreased expression of IGF-1 and IRS-1. Key words: Fatty liver; Dietary fats, unsaturated; Insulin-like growth factor 1; Insulin receptor substrate proteins

The Beneficial Impact of Antidepressant Drugs on Prenatal Stress-Evoked Malfunction of the Insulin-Like Growth Factor-1 (IGF-1) Protein Family in the Olfactory Bulbs of Adult Rats.

Insulin-like growth factor-1 (IGF-1) promotes the growth, differentiation, and survival of both neurons and glial cells, and it is believed to exert antidepressant-like activity. Thus, disturbances in the IGF-1 system could be responsible for the course of depression. To date, there have been no papers showing the impact of chronic antidepressant treatment on the IGF-1 network in the olfactory bulb (OB) in an animal model of depression. Prenatal stress was used as model of depression. Twenty-four 3-month-old male offspring of control and stressed mothers were subjected to behavioral testing (forced swim test). The mRNA expression of IGF-1 and IGF-1 receptor (IGF-1R) and the protein level of IGF-1 and its phosphorylation, as well as the concentrations of IGF-binding proteins (IGFBP-2, -4, -3, and -6), were measured in OBs before and after chronic imipramine, fluoxetine, or tianeptine administration. Adult rats exposed prenatally to stressful stimuli displayed not only depression-like behavior but also decreased IGF-1 expression, dysregulation in the IGFBP network, and diminished mRNA expression, as well as IGF-1R phosphorylation, in the OB. The administration of antidepressants normalized most of the changes in the IGF-1 system of the OB evoked by prenatal stress. These results suggested a beneficial effect of chronic antidepressant drug treatment in the alleviation of IGF-1 family malfunction in OBs in an animal model of depression.

RNAi-mediated gene silencing of ST6GalNAc I suppresses the metastatic potential in gastric cancer cells.

ST6GalNAc I is a sialyltransferase controlling the expression of sialyl-Tn antigen (STn), which is overexpressed in several epithelial cancers, including gastric cancer, and is highly correlated with cancer metastasis. However, the functional contribution of ST6GalNAc I to development or progression of gastric cancer remains unclear. In this study, we investigated the effects of suppression of ST6GalNAc I on gastric cancer in vitro and in vivo. Gastric cancer cell lines were transfected with ST6GalNAc I siRNA and were examined by cell proliferation, migration, and invasion assays. We also evaluated the effect of ST6GalNAc I siRNA treatment in a peritoneal dissemination mouse model. The differences in mRNA levels of selected signaling molecules were analyzed by polymerase chain reaction (PCR) arrays associated with tumor metastasis in MKN45 cells. The signal transducer and activator of transcription 5b (STAT5b) signaling pathways that reportedly regulate the insulin-like growth factor-1 (IGF-1) were analyzed by Western blot. ST6GalNAc I siRNA inhibited gastric cancer cell growth, migration, and invasion in vitro. Furthermore, intraperitoneal administration of ST6GalNAc I siRNA- liposome significantly inhibited peritoneal dissemination and prolonged the survival of xenograft model mice with peritoneal dissemination of gastric cancer. PCR array confirmed that suppression of ST6GalNAc I caused a significant reduction in expression of IGF-1 mRNA. Decreased IGF-1 expression in MKN45 cells treated with ST6GalNAc I siRNA was accompanied by reduced phosphorylation of STAT5b. ST6GalNAc I may regulate the gene expression of IGF-1 through STAT5b activation in gastric cancer cells and may be a potential target for treatment of metastasizing gastric cancer.

Adeno-associated virus-mediated insulin-like growth factor-1 in the treatment of diabetic cystopathy

Objective To study the curative treatment role of the recombinant adeno-associated virus (rAAV)-mediated rat insulin-like growth factor-1 (IGF-1) gene on streptozotocin-induced diabetic cystopathy.Methods Forty male SD rats were divided randomly into five age-matched groups:normal control (CN,n =8),diabetes model (DM,n =8),rAAV2/1-IGF-1 transduction model (IGF-1,n =8),insulin therapy model (INS,n =8),rAAV2/1-IGF-1 transduction & insulin therapy model group (IGF-1 + INS,n =8).Eight weeks after the induction of diabetes model,insulin (6 U) and/or rAAV2/1-IGF-1 (100 μ1) was injected into rats of corresponding groups.Urinary dynamics was analyzed to evaluate the bladder function after gene therapy for 6 weeks.HE staining was used to observe the pathological changes of bladder detrusor.The expression profile of IGF-1 protein was assessed by using immunohistochemistry (IHC).Results As compared with DM group,the voiding rate in IGF-1 + INS group,INS group and IGF-1 group was significantly increased (86.59 ± 1.20,79.18 ± 1.34,77.88 ± 1.82 vs.76.16 ± 1.87,P ＜ 0.05).Detrusor muscle in DM group showed bundles derangement,loose structure,but detrusor injury severity in IGF-1 group and INS group was significantly relieved,and detusor structure performance inIGF-1 + INS group was close to the normal level.The IGF-1 expression level in bladder tissue was significantly decreased in DM group (3.37 ± 0.52) as compared with IGF-1 + INS group (4.16 ± 0.15),INS group (4.08 ± 0.30) and IGF-1 group (4.12 ± 0.35).Conclusion The decreased IGF-1 expression levels in bladder tissue may be involved in the development of diabetic cystopathy.IGF-1 gene and INS treatment may play a part role in repairing bladder function of diabetic rats. Key words: Adeno-associated virus; Insulin-like growth factor-1; Diabetes; Cystopathy