Insulin-like Growth Factor II Research Articles

Rab9-dependent autophagy is required for the IGF-IIR triggering mitophagy to eliminate damaged mitochondria.

Mitochondria dysfunction is the major characteristic of mitophagy, which is essential in mitochondrial quality control. However, excessive mitophagy contributes to cell death in a number of diseases, including ischemic stroke and hepatotoxicity. Insulin-like growth factor II (IGF-II) and its receptor (IGF-IIR) play vital roles in the development of heart failure during hypertension. We found that IGF-II triggers IGF-IIR receptor activation, causing mitochondria dysfunction, resulting in mitophagy, and cardiomyocyte cell death. These results indicated that IGF-IIR activation triggers mitochondria fragmentation, leading to autophagosome formation, and loss of mitochondria content. These results are associated with Parkin-dependent mitophagy. Additionally, autophagic proteins Atg5, and Atg7 deficiency did not suppress IGF-IIR-induced mitophagy. However, Rab9 knockdown reduced mitophagy and maintained mitochondrial function. These constitutive mitophagies through IGF-IIR activation trigger mitochondria loss and mitochondrial ROS accumulation for cardiomyocyte viability decrease. Together, our results indicate that IGF-IIR predominantly induces mitophagy through the Rab9-dependent alternative autophagy.

RETRACTED: Inflammatory-Related P62 Triggers Malignant Transformation of Mesenchymal Stem Cells through the Cascade of CUDR-CTCF-IGFII-RAS Signaling

Inflammatory and autophagy-related gene P62 is highly expressed in most human tumor tissues. Herein, we demonstrate that P62 promotes human mesenchymal stem cells’ malignant transformation via the cascade of P62-tumor necrosis factor alpha (TNF-α)-CUDR-CTCF-insulin growth factor II (IGFII)-H-Ras signaling. Mechanistically, we reveal P62 enhances IGFII transcriptional activity through forming IGFII promoter-enhancer chromatin loop and increasing METTL3 occupancy on IGFII 3′ UTR and enhances H-Ras overexpression by harboring inflammation-related factors, e.g., TNFR1, CLYD, EGR1, NFκB, TLR4, and PPARγ. Furthermore, the P62 cooperates with TNF-α to promote malignant transformation of mesenchymal stem cells. These findings, for the first time, provide insight into the positive role that P62 plays in malignant transformation of mesenchymal stem cells and reveal a novel link between P62 and the inflammation factors in mesenchymal stem cells.

In vivo inhibition of nuclear factor of activated T-cells leads to atherosclerotic plaque regression in IGF-II/LDLR-/-ApoB100/100 mice.

Aims:Despite vast clinical experience linking diabetes and atherosclerosis, the molecular mechanisms leading to accelerated vascular damage are still unclear. Here, we investigated the effects of nuclear factor of activated T-cells inhibition on plaque burden in a novel mouse model of type 2 diabetes that better replicates human disease.Methods & Results:IGF-II/LDLR–/–ApoB100/100 mice were generated by crossbreeding low-density lipoprotein receptor–deficient mice that synthesize only apolipoprotein B100 (LDLR–/–ApoB100/100) with transgenic mice overexpressing insulin-like growth factor-II in pancreatic β cells. Mice have mild hyperglycaemia and hyperinsulinaemia and develop complex atherosclerotic lesions. In vivo treatment with the nuclear factor of activated T-cells blocker A-285222 for 4 weeks reduced atherosclerotic plaque area and degree of stenosis in the brachiocephalic artery of IGF-II/LDLR–/–ApoB100/100 mice, as assessed non-invasively using ultrasound biomicroscopy prior and after treatment, and histologically after termination. Treatment had no impact on plaque composition (i.e. muscle, collagen, macrophages). The reduced plaque area could not be explained by effects of A-285222 on plasma glucose, insulin or lipids. Inhibition of nuclear factor of activated T-cells was associated with increased expression of atheroprotective NOX4 and of the anti-oxidant enzyme catalase in aortic vascular smooth muscle cells.Conclusion:Targeting the nuclear factor of activated T-cells signalling pathway may be an attractive approach for the treatment of diabetic macrovascular complications.

Potential role of insulin receptor isoforms and IGF receptors in plaque instability of human and experimental atherosclerosis

BackgroundClinical complications associated with atherosclerotic plaques arise from luminal obstruction due to plaque growth or destabilization leading to rupture. We previously demonstrated that overexpression of insulin receptor isoform A (IRA) and insulin-like growth factor-I receptor (IGF-IR) confers a proliferative and migratory advantage to vascular smooth muscle cells (VSMCs) promoting plaque growth in early stages of atherosclerosis. However, the role of insulin receptor (IR) isoforms, IGF-IR or insulin-like growth factor-II receptor (IGF-IIR) in VSMCs apoptosis during advanced atherosclerosis remains unclear.MethodsWe evaluated IR isoforms expression in human carotid atherosclerotic plaques by consecutive immunoprecipitations of insulin receptor isoform B (IRB) and IRA. Western blot analysis was performed to measure IGF-IR, IGF-IIR, and α-smooth muscle actin (α-SMA) expression in human plaques. The expression of those proteins, as well as the presence of apoptotic cells, was analyzed by immunohistochemistry in experimental atherosclerosis using BATIRKO; ApoE−/− mice, a model showing more aggravated vascular damage than ApoE−/− mice. Finally, apoptosis of VSMCs bearing IR (IRLoxP+/+ VSMCs), or not (IR−/− VSMCs), expressing IRA (IRA VSMCs) or expressing IRB (IRB VSMCs), was assessed by Western blot against cleaved caspase 3.ResultsWe observed a significant decrease of IRA/IRB ratio in human complicated plaques as compared to non-complicated regions. Moreover, complicated plaques showed a reduced IGF-IR expression, an increased IGF-IIR expression, and lower levels of α-SMA indicating a loss of VSMCs. In experimental atherosclerosis, we found a significant decrease of IRA with an increased IRB expression in aorta from 24-week-old BATIRKO; ApoE−/− mice. Furthermore, atherosclerotic plaques from BATIRKO; ApoE−/− mice had less VSMCs content and higher number of apoptotic cells. In vitro experiments showed that IGF-IR inhibition by picropodophyllin induced apoptosis in VSMCs. Apoptosis induced by thapsigargin was lower in IR−/− VSMCs expressing higher IGF-IR levels as compared to IRLoxP+/+ VSMCs. Finally, IRB VSMCs are more prone to thapsigargin-induced apoptosis than IRA or IRLoxP+/+ VSMCs.ConclusionsIn advanced human atherosclerosis, a reduction of IRA/IRB ratio, decreased IGF-IR expression, or increased IGF-IIR may contribute to VSMCs apoptosis, promoting plaque instability and increasing the risk of plaque rupture and its clinical consequences.

Takifugu rubripes cation independent mannose 6-phosphate receptor: Cloning, expression and functional characterization of the IGF-II binding domain

Mannose 6-phosphate/IGF-II receptor mediated lysosomal clearance of insulin-like growth factor-II is significantly associated with the evolution of placental mammals. The protein is also referred to as the IGF-II receptor. Earlier studies suggested relatively low binding affinity between the receptor and ligand in prototherian and metatherian mammals. In the present study, we cloned the IGF-II binding domain of the early vertebrate fugu fish and expressed it in bacteria. A 72000Da truncated receptor containing the IGF-II binding domain was obtained. Analysis of this protein (covering domains 11–13 of the CIMPR) for its affinity to fish and human IGF-II by ligand blot assays and ELISA showed that the expressed receptor can specifically bind to both fish and human IGF-II. Additionally, a peptide-specific antibody raised against the region of the IGF-II binding domain also was able to recognize the IGF-II binding regions of mammalian and non-mammalian cation independent MPR protein. These interactions were further characterized by Surface Plasma resonance support that the receptor binds to fish IGF-II, with a dissociation constant of 548nM. Preliminary analysis suggests that the binding mechanism as well as the affinity of the fish and human receptor for IGF-II may have varied according to different evolutionary pressures.

Promotion of Insulin-like growth factor II in cell proliferation and epithelial-mesenchymal transition in hepatocellular carcinoma.

This study aims to investigate the involvement of insulin-like growth factor II (IGF-II) in human hepatocellular carcinoma (HCC) proliferation and metastasis. The effects of IGF-II on cell proliferation, cell cycle, apoptosis, cell migration, and invasion in HCC Huh7 cells were investigated in the study. IGF-II promoted cell proliferation and colony formation, suppressed cell apoptosis in Huh7 cells by promoting cell cycle progression, induced epithelial-mesenchymal transition (EMT) phenotypes, and enhanced the metastatic potential of HCC in vitro. Our results revealed that IGF-II promotes cell proliferation and EMT in HCC cells.

The expression level of vascular endothelial growth factor receptor-2, vascular endothelial growth factor receptor-3, and insulin-like growth factor II mRNA binding protein 3 in renal cell carcinoma: Can these markers indicate poor prognosis in immunohistochemical examination?

Background: The malignant tumors of the kidney are the most aggressive among urologic cancers. To treat patients with renal cell carcinoma (RCC), it is important to understand the disease's prognostic factors. Angiogenesis is an essential process, responsible for the growing, and spreading of neoplastic tissues. Vascular endothelial growth factor (VEGF), the most potent angiogenetic factor known, and its receptor VEGF (VEGFR) play an important role in angiogenesis. Insulin-like growth factor-II mRNA binding protein 3 (IMP-3) is found in some malignant tumors and contributes to cell growth and cell migration during the early stages of embryogenesis. Material and Methods: The following study retrospectively evaluated 48 radical, 29 simple, and 23 partial nephrectomy specimens with RCC. Pathologic prognostic parameters, including tumor size, tumor stage, Fuhrman nuclear grade, distant metastasis status, and lymph node involvement status were compared with the immunohistochemical expression levels of VEGFR-2, VEGFR-3, and IMP-3. Results: Except the relation between VEGFR-3 and Fuhrman nuclear grade, there was no significant relation with the expressions of VEGFR-2, VEGFR-3, and IMP-3 and the pathologic prognostic parameters such as tumor size, tumor stage, Fuhrman nuclear grade, distant metastasis status, and lymph node involvement status. All three markers showed significant expression in almost all chromophobe and papillary histologic subtypes. The expression rates for chromophobe, papillary type 1, and type 2 RCC were 100%, 90%, and 100% for VEGFR-2, respectively, and 87.5%, 90%, and 100% for VEGFR-3, respectively. The expression rates of IMP-3 were 50% for papillary type 1, 83.3% for papillary type 2, and 100% for chromophobe RCC. Conclusion: Although the limited number of cases, current data gathered from our study shows that these markers have no relation with pathologic prognostic parameters and would not provide additional information in the immunohistochemical examination. Anyway, their tendency of expression in chromophobe and papillary type RCC is remarkable which should be evaluated with a larger number of cases.

Insulin-Like Growth Factor II Targets the mTOR Pathway to Reverse Autism-Like Phenotypes in Mice

Autism spectrum disorder (ASD) is a developmental disability characterized by impairments in social interaction and repetitive behavior, and is also associated with cognitive deficits. There is no current treatment that can ameliorate most of the ASD symptomatology; thus, identifying novel therapies is urgently needed. We used male BTBR T+Itpr3tf /J (BTBR) mice, a model that reproduces most of the core behavioral phenotypes of ASD, to test the effects of systemic administration of insulin-like growth factor II (IGF-II), a polypeptide that crosses the blood-brain barrier and acts as a cognitive enhancer. We show that systemic IGF-II treatments reverse the typical defects in social interaction, cognitive/executive functions, and repetitive behaviors reflective of ASD-like phenotypes. In BTBR mice, IGF-II, via IGF-II receptor, but not via IGF-I receptor, reverses the abnormal levels of the AMPK-mTOR-S6K pathway and of active translation at synapses. Thus, IGF-II may represent a novel potential therapy for ASD.SIGNIFICANCE STATEMENT Currently, there is no effective treatment for autism spectrum disorder (ASD), a developmental disability affecting a high number of children. Using a mouse model that expresses most of the key core as well as associated behavioral deficits of ASD, that are, social, cognitive, and repetitive behaviors, we report that a systemic administration of the polypeptide insulin-like growth factor II (IGF-II) reverses all these deficits. The effects of IGF-II occur via IGF-II receptors, and not IGF-I receptors, and target both basal and learning-dependent molecular abnormalities found in several ASD mice models, including those of identified genetic mutations. We suggest that IGF-II represents a potential novel therapeutic target for ASD.

IMP2 and IMP3 cooperate to promote the metastasis of triple-negative breast cancer through destabilization of progesterone receptor

Triple-negative breast cancer (TNBC) is one of the most aggressive malignancies and is associated with high mortality rates due to the lack of effective therapeutic targets. In this study, we demonstrated that insulin-like growth factor-II mRNA-binding protein 2 and 3 (IMP2 and IMP3) are specifically overexpressed in TNBC and cooperate to promote cell migration and invasion. Downregulation of both IMP2 and IMP3 in TNBC cells was found to produce a synergistic effect in suppressing cell invasion and invadopodia formation, whereas overexpression of IMP2 and IMP3 in luminal subtype cells enhanced epithelial-mesenchymal transition and metastasis. We also showed that IMP2 and IMP3 are direct targets of microRNA-200a (miR-200a), which is downregulated in TNBC. Conversely, IMP2 and IMP3 suppressed the transcription of miR-200a by destabilizing progesterone receptor (PR) mRNA through recruitment of the CCR4-NOT transcription complex subunit 1 (CNOT1) complex. Together, our findings suggest that IMP2 and IMP3 partially determine the characteristic phenotype and synergistically promote the metastasis of TNBC by downregulating PR. The identified IMP2/3-miR-200a-PR axis represents a novel double-negative feedback loop and serves as a new potential therapeutic target for the treatment of TNBC.

Expression and characterization of insulin-like growth factor II mRNA binding protein in the razor clam Sinonovacula constricta

Insulin-like growth factor-II mRNA binding protein (igf2bp) is an mRNA binding protein that regulates the post-transcriptional fate of multiple transcripts. In this study, a novel igf2bp gene was identified in the razor clam Sinonovacula constricta. The complete 2254 bp Sc-igf2bp cDNA consists of an open reading frame (ORF) encoding 610 amino acid (aa) residues. The deduced protein includes a single RNA recognition motif (RRM) and four K homology (KH) domains. Sc-igf2bp transcripts were expressed widely during different developmental stages and in adult tissues, and a 95 kDa recombinant pEGX-4T-1-Sc-igf2bp protein was expressed in Escherichia coli Rosetta (DE3) pLysS cells and purified using Glutathione Sepharose 4B resin. Activity was evaluated by GST pull-down assays, and mass spectrometry results indicated that Sc-igf2bp may participate in RNA-related processes. The findings provide a basis for further research on the role of igf2bp in regulating the growth and development of the razor clam.

MiR-483-5p promotes IGF-II transcription and is associated with poor prognosis of hepatocellular carcinoma.

The human insulin-like growth factor-II (IGF-II) gene transcribes four mRNAs (P1 mRNA-P4 mRNA), and P3 mRNA overexpression contributes to hepatocarcinogenesis. IGF-II-derived miR-483-5p is implicated in the development of cancers. Here, we investigated the involvement of miR-483-5p in P3 mRNA overexpression regulation and its role in hepatocellular carcinoma. Our results showed that miR-483-5p up-regulated P3 mRNA transcription by targeting the 5′-untranslated region (5′UTR) of P3 mRNA in hepatocellular carcinoma. The mechanism was involved in recruiting of an argonaute 1(Ago1)-argonaute 2 (Ago2) complex to the P3 mRNA 5′UTR and the P3 promoter of IGF-II gene by miR-483-5p, accompanied by increased enrichment of RNA polymerase II and activating histone marks histone 3 lysine 4 trimethylation (H3K4me3), histone 3 lysine 27 acetylation (H3K27ac), and histone 4 lysine 5/8/12/16 acetylation (H4Kac) at the P3 promoter. High miR-483-5p expression was an independent predictor for shorter survival of HCC patients. The findings suggest that miR-483-5p promotes P3 mRNA transcription by recruiting the Ago1-Ago2 complex to the P3 mRNA 5′UTR and is associated with poor prognosis of HCC. Our results display a potential new model for miRNAs to up-regulate gene expression.

Effect of Dietary Fish Oil Replacement with Plant Oils on Growth Performance and Gene Expression in Juvenile Rainbow Trout (Oncorhynchus mykiss)

Abstract An eight-week feeding trial was conducted to evaluate the effects of total (100%) replacement of dietary fish oil with alternative lipid sources in juvenile rainbow trout. Six iso-nitrogenous and iso-lipidic experimental diets were formulated: CO (14%) – cod liver oil; SSO (14%) – safflower seed oil; SBO (14%) – soybean oil; LO (14%) – linseed oil; SBO (7%) + LO (7%) – a blend of soybean oil and linseed oil; and SSO (7%) + LO (7%) – a blend of safflower seed oil and linseed oil. Growth performance [specific growth rate (SGR), weight gain (WG), food conversion ratio (FCR) and survival rate (SR)], growth hormones [growth hormone (GH-I), insulin-like growth factor-I (IGF-I) and insulin-like growth factor-II (IGF-II)], immune transforming growth factor-β (TGF-β) and antioxidant [superoxide dismutase (SOD), glutathione peroxidase (GPx), glutathione reductase (GR), catalase (CAT) and glutathione S-transferase (GST)] response, and heat shock protein 70 (HSP70) mRNA levels were determined in muscle and liver. Our data indicated that final weight, weight gain, FCR and SGR showed significant difference among the six dietary treatments (P<0.05) while there were no significant differences in survival rate between the rainbow trout from supplement fed groups and control group. HSP70 mRNA level expression in muscle was higher in fish fed SSO (P<0.05) while highest level in liver was obtained from fish fed SBO compared to the other treatments (P<0.05). There were no significant differences among treatments for TGF-β mRNA expression level in muscle and liver. In conclusion, growth performance and expression levels of growth hormones, antioxidants, HSP70, except TGF-β were affected by five separate lipid sources. In addition, LO positively increased growth performance of juvenile rainbow trout by means of preventing oxidative stress and HSP70 and, enhanced expression of growth hormone related gene.

Gene Effects on Body Weight, Carcass Yield, and Meat Quality of Thai Indigenous Chicken.

The selection of rapidly growing animals in breeding programs has had inadvertent detrimental effects on meat quality. Thus, the aim of the present study was to investigate the relationship between body weight (BW) and meat quality traits, and the effects of genes encoding insulin-like growth factor I (IGF-I), insulin-like growth factor II (IGF-II), melanocortin-4 receptor (MC4R), and calpain 1 (CAPN1) on BW, carcass yield, and meat quality of the Thai indigenous chicken, Leung Hang Khao. Five hundred and ten chickens were used for genotyping. PCR-restriction fragment length polymorphism and PCR-single strand conformation polymorphism were used to determine the genotypes of IGF-I, IGF-II, MC4R, and CAPN1. BWs were collected from 0–16 weeks of age. The chickens were sacrificed at 16 weeks and individual carcass yields and meat qualities (drip loss, cooking loss, and shear force) were recorded. The correlations between BW and meat qualities were determined. Significant correlation between BW and cooking loss and shear force of breast meat and between BW and drip loss of thigh meat were detected (P<0.05); however, the magnitude of the association was low (−0.1–0.1). IGF-I was eliminated from the association analysis because genotype AA was lost and the frequency of occurrence of the AC genotype was low (0.04). Significant associations between IGF-II, CAPN1, and BW, and CAPN1 and meat quality were detected, while non-significant association between MC4R and BW was observed. The results indicated a low, negative relationship between BW and meat quality, and that the IGF-II and CAPN1 could be used as genetic markers in Leung Hang Khao chickens to improve growth and meat quality through breeding.

Nulliparity is associated with subtle adverse metabolic outcomes in overweight/obese mothers and their offspring.

We aimed to evaluate metabolic outcomes in overweight/obese nulliparous and multiparous women and their offspring. Seventy-two overweight and obese women who participated in a randomized controlled trial of exercise in pregnancy were included in the study, comparing 18 nulliparous and 54 multiparous women and their singleton offspring. Women were assessed at 19 and 36weeks of gestation. Fetal growth was measured using standard obstetric ultrasound techniques. Cord blood was collected at birth. Maternal and offspring body composition was assessed using DXA ~2weeks after delivery. Nulliparous women had higher HbA1c in the third trimester of pregnancy than multiparous women (5.48% vs 5.29%; P=.002) and were more insulin-resistant based on the surrogate marker sex hormone-binding globulin (354 vs 408nmol/L; P=.047). Nulliparous women also had higher levels of the inflammatory marker tumour necrosis factor-alpha (4.74 vs 3.62pg/mL; P=.025). At birth, the offspring of nulliparous women were on average 340g (P=.013) and 0.69 standard deviation scores (P=.026) lighter than those born of multiparous women. Cord blood data showed lower insulin-like growth factor-II (P=.026) and higher IGF binding protein-1 (P=.002) levels in the offspring of nulliparous women. In addition, a less favourable metabolic profile was observed in the offspring of nulliparous women, as indicated by higher triglyceride (P<.001) and interleukin-6 (P=.039) concentrations. Infants born of nulliparous overweight and obese women appear to be exposed to a less favourable metabolic environment in utero, with evidence of subtle adverse metabolic outcomes at birth compared to infants of overweight/obese multiparous women.

Insulin-like growth factor II mRNA binding protein 3 expression in the non-muscle invasive bladder cancer and its relationships with the prognosis

Objective To investigate the expression of insulin-like growth factor Ⅱ mRNA binding protein 3 (IMP3) in non-muscle invasive bladder cancer and its relationship with the tumor recurrence and progression. Methods IMP3 protein expression was detected by immunohistochemistry in 130 cases of non-muscle invasive bladder cancer specimens who underwent transurethral resection the first time at Beijing Chao-Yang hospital, from October 2010 to October 2013. Besides, we analyzed 20 cases of muscle-invasive samples and 20 benign tissues adjacent to cancer as control. The 130 patients were followed up by telephone and other methods. According to the UICC-TNM standard.Survival analysis was calculated by using the Kaplan-Meier method, and the difference in survival curves was analyzed by using the log-rank test. For multiple analyses, The Cox proportional hazards regression model was used. Results The positive expression rate of IMP3 in 130 patients with non-muscle invasive bladder cancer was 59.2% (77/130), of which 30.0% (39/130) was weak expression, 29.2% (38/130) was strong. However there was 80.0% (16 /20) in muscle-invasive specimens, of which 20.0% (4/20) was weak, 60.0% (12/20) was strong (P=0.011). IMP3 was not detected in all benign tissues adjacent to cancer (P<0.001). All the 130 patients were followed-up for 5 to 69 months , 45 cases experienced disease recurrence, 20 patients had progressed and 12 cases died.IMP3 expression was significantly related to higher tumor stage (P<0.001), high tumor grade (P=0.014), and tumor recurrence (P=0.003). Kaplan-Meier plots and log-rank tests showed that patients with IMP3-positive tumors had a lower disease-free survival (P=0.002) and progression-free survival rate (P=0.010) than those with IMP3-negative tumors. In the multivariable Cox analysis, we found that IMP3 protein was an independent predictor of disease-free survival (P=0.010) in non-muscle invasive urothelial carcinoma of bladder. Conclusions IMP3 was not expressed in benign tissue adjacent to cancer, whereas highly expressed in bladder cancer, and high IMP3 expression is an independent prognostic factor in NMIBC that can identify the patients with a high potential to relapse. Key words: Insulin-like growth factor Ⅱ mRNA binding protein 3(IMP3); Non-muscle invasive bladder cancer(NMIBC); Prognosis

IGF2BP3 as a potential tissue marker for the diagnosis of esophageal high-grade intraepithelial neoplasia.

BackgroundThe clinical significance of insulin-like growth factor-II mRNA-binding protein-3 (IGF2BP3) in esophageal high-grade intraepithelial neoplasia (HGIN) is not clear. This study was designed to characterize the expression of IGF2BP3 in HGIN.Patients and methodsIGF2BP3 expression was evaluated by Western blot analyses in 12 cases and by immunohistochemistry (IHC) in 112 cases. The associations between IGF2BP3 expression in HGIN and the clinicopathological parameters were examined.ResultsModerate to strong IGF2BP3 expression was present in HGIN samples. Using IHC, it was found that IGF2BP3 was positive in 68 (60.71%) cases. Intense IHC of IGF2BP3 in HGIN was associated with a deeper lesion depth, and the lesion depth was the only predictor of the positive expression of IGF2BP3.ConclusionOur results suggested that IGF2BP3 may be a supplementary tissue marker for preoperative diagnosis of HGIN.

IMP3 Immunoreactivity is More Sensitive Than AMACR in Detecting Dysplastic Epithelium and Early Adenocarcinoma in Barrett Esophagus.

α-methylacyl coenzyme A racemase (AMACR) and insulin-like growth factor-II mRNA-binding protein 3 (IMP3) are 2 markers helpful in detecting difficult cases of dysplasia in Barrett esophagus (BE). However, no comparison studies have been performed to assess their performance in the same patient population. The aim of our study was to compare the immunohistochemical expression of IMP3 and AMACR in dysplastic lesions and early adenocarcinoma (EAC) arising in BE and evaluate their sensitivity and specificity. A total of 98 cases [BE negative for dysplasia, n=24; indefinite for dysplasia (BE-IND), n=18; low-grade dysplasia (LGD), n=24; high-grade dysplasia (HGD), n=16; and EAC, n=16] were immunostained for AMACR and IMP3 and evaluated for the degree, the extent, and the intensity of staining. No immunoreactivity for AMACR or IMP3 was observed in all 24 cases of BE negative for dyplasia. One of 18 (5.5%) cases of BE-IND was positive for IMP3, but all were negative for AMACR. AMACR and IMP3 were positive in 16.7% versus 41.7 % of the cases with BE-LGD, 25% versus 62.5% of BE-HGD, and 62.5% versus 93.7% of EAC, respectively. The sensitivity of AMACR and IMP3 for the detection of dysplasia in BE is 16.7% and 41.7% for LGD, 25% and 62.5% for HGD, and 62.5% and 93.7% in EAC, respectively. The specificity is 100% for both markers. In addition, a comparison of the intensity of reactivity shows a better result with IMP3 (36/98, 36.7%) than with AMACR (18/98, 18.4%) (P<0.001). IMP3 has a similar specificity, but a better sensitivity, intensity, and extent of reactivity in comparison with AMACR, and may be used as an alternative to AMACR, in support of the diagnosis of BE-dysplasia and EAC.

The behavioral deficits and cognitive impairment are correlated with decreased IGF-II and ERK in depressed mice induced by chronic unpredictable stress

ABSTRACTAim: To investigate the behavioral deficits, cognitive impairment and possible mechanisms induced by chronic unpredictable stress (CUS) in mice of different ages.Methods: The behaviors and cognition were tested using the open field test, tail suspension test and the Morris water maze. The changes in the insulin-like growth factor II (IGF-II) and the extracellular signal-regulated kinase (ERK) and phosphorylation (p-ERK) in the hippocampus (HP) and prefrontal cortex (PFC) were evaluated by immunohistochemistry.Results: The 15-month-old mice revealed a significant decline in spontaneous behavior and the learning–memory function and showed a decrease in IGF-II and p-ERK expression levels in HP and PFC. Four weeks of CUS exposure induced significant anxiety- and depression-like behavior and learning–memory function impairment in 3- to 15-month-old mice, and reduced IGF-II and p-ERK expression levels in HP and PFC, compared with control group mice, respectively.Conclusions: The behavioral deficits and cognitive impairment induced by CUS and aging in mice could be associated with the down-regulated expression of IGF-II and p-ERK in HP and PFC. This role seems to be dependent on the intracellular ERK pathway.

IGF-II promotes neuroprotection and neuroplasticity recovery in a long-lasting model of oxidative damage induced by glucocorticoids

Insulin-like growth factor-II (IGF-II) is a naturally occurring hormone that exerts neurotrophic and neuroprotective properties in a wide range of neurodegenerative diseases and ageing. Accumulating evidence suggests that the effects of IGF-II in the brain may be explained by its binding to the specific transmembrane receptor, IGFII/M6P receptor (IGF-IIR). However, relatively little is known regarding the role of IGF-II through IGF-IIR in neuroprotection. Here, using adult cortical neuronal cultures, we investigated whether IGF-II exhibits long-term antioxidant effects and neuroprotection at the synaptic level after oxidative damage induced by high and transient levels of corticosterone (CORT). Furthermore, the involvement of the IGF-IIR was also studied to elucidate its role in the neuroprotective actions of IGF-II. We found that neurons treated with IGF-II after CORT incubation showed reduced oxidative stress damage and recovered antioxidant status (normalized total antioxidant status, lipid hydroperoxides and NAD(P) H:quinone oxidoreductase activity). Similar results were obtained when mitochondria function was analysed (cytochrome c oxidase activity, mitochondrial membrane potential and subcellular mitochondrial distribution). Furthermore, neuronal impairment and degeneration were also assessed (synaptophysin and PSD-95 expression, presynaptic function and FluoroJade B® stain). IGF-II was also able to recover the long-lasting neuronal cell damage. Finally, the effects of IGF-II were not blocked by an IGF-IR antagonist, suggesting the involvement of IGF-IIR. Altogether these results suggest that, in or model, IGF-II through IGF-IIR is able to revert the oxidative damage induced by CORT. In accordance with the neuroprotective role of the IGF-II/IGF-IIR reported in our study, pharmacotherapy approaches targeting this pathway may be useful for the treatment of diseases associated with cognitive deficits (i.e., neurodegenerative disorders, depression, etc.).

IGF2BP1: a novel binding protein of p38 MAPK.

Signal transduction pathways control various biological processes in cells leading to distinct cellular functions. Protein-protein interactions and post-translational modifications are the physiological events that occur in signaling pathway. p38 MAPK are known to be involved in regulating wide range of cellular processes by interacting and activating relevant signaling molecules by means of phosphorylation. Deregulation of p38 MAPK is associated with various pathological conditions. In order to get an insight into the role played by p38 MAPK in cellular signaling, studies were carried out to identify proteins that interact with p38 MAPK. Mass spectrometry was used to identify the proteins present in p38 MAPK complex obtained by co-immunoprecipitation. Based on mass spectrometry data, here we report insulin-like growth factor-II binding protein 1 (IGF2BP1) as a novel interacting partner of p38 MAPK. IGF2BP1 is a RNA-binding protein predominantly known to be involved in tumor progression. To reconfirm the mass spectrometry data, in silico analysis was carried out. Based on different models predicted in silico, we report the possible interaction domains of p38MAPK and IGF2BP1. Considering the involvement of p38MAPK and IGF2BP1 in cancer, our study opens up the possibility of p38MAPK regulating IGF2BP1 function, and the possibility of targeting this novel interaction for developing cancer-treating drugs is discussed.