Role Of Insulin-like Growth Factor Research Articles

Role of insulin-like growth factor 1 in pathogenesis of acne vulgaris: relation to acne severity and body mass index

<div class="Section1"><p class="abstract"><strong>Background:</strong> Acne vulgaris is a multifactorial skin disease. A potential role for insulin-like growth factor-1 (IGF-1) has been suggested in the pathogenesis of acne. Several studies have shown that elevated levels of serum IGF-1 correlate with overproduction of sebum and acne. Objective: Measurement of the serum level of IGF-1 in acne patients in comparison to normal controls and evaluating the relationship of these levels to severity of acne and body mass index (BMI), in order to investigate the role of this factor in the pathogenesis of acne.</p><p class="abstract"><strong>Methods:</strong> Fifty-four patients with acne vulagaris and 42 healthy controls were included. History taking, dermatological examination, clinical assessments of acne severity, calculation of BMI were performed for patients. Blood samples were collected from all participants for estimation of serum IGF-1 level using enzyme linked immunosorbant assay.<strong></strong></p><p class="abstract"><strong>Results:</strong> There was a significantly higher serum IGF-1 level in acne patients (p<0.05) than controls. Authors didn’t find a relation of significance between elevated serum IGF-1 level and degree of acne severity and BMI (p>0.05). There was a significant positive correlation between serum IGF-1 level and age of the patients.</p><p class="abstract"><strong>Conclusions:</strong> There is a significantly higher serum IGF-1 in acne patients than controls not related to acne severity and BMI. That is adding to the scientific evidence of IGF-1 role in pathogenesis of acne vulgaris.</p></div>

Rola insulinopodobnego czynnika wzrostu 1 w patogenezie nowotworów i chorób zapalnych skóry

Rola insulinopodobnego czynnika wzrostu 1 w patogenezie nowotworów i chorób zapalnych skóry

Role of Akt and mammalian target of rapamycin signalling in insulin-like growth factor 1-mediated cell proliferation in porcine Sertoli cells.

The critical role of insulin-like growth factor (IGF) 1 in promoting Sertoli cell proliferation invivo and invitro has been established, but its downstream signalling mechanisms remain unknown. In addition to mitogenic effects, a role for IGF1 in mediating cholesterol biosynthesis within testes has been implied. The aims of this study were to investigate the roles of: (1) phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin (mTOR) signalling in IGF1-mediated Sertoli cell proliferation; and (2) IGF1 in mediating cholesterol biosynthesis in Sertoli cells. Primary cultures of Sertoli cells were prepared from 1-week-old porcine testes. On Day 3 of culture, Sertoli cells were treated with 300ng mL-1 IGF1, alone or in combination with inhibitors of IGF1 receptor (2μM picropodophyllotoxin), Akt (1μM wortmannin) or mTOR (200nM rapamycin). Cells were cultured for 30min and phosphorylation levels of Akt, mTOR and p70 ribosomal protein S6 kinase (p70S6K) were determined by immunoblotting. Cell proliferation and quantitative polymerase chain reaction assays were conducted using cells cultured for 24h. IGF1 increased phosphorylation of Akt, mTOR and p70S6K and cell proliferation, and these effects were inhibited by inhibitors of IGF1R, Akt and mTOR. Furthermore, IGF1 upregulated the expression of cholesterol biosynthetic genes (3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), 3-hydroxy-3-methylglutaryl-CoA synthase (HMGCS1) and cytochrome P450, family 5, subfamily A, polypeptide 1 (CYP5A1)), but not sterol regulatory element-binding transcription factor 1 (SREBF1). Increased phosphorylation of p70S6K, a major downstream target of mTOR, and upregulated expression of genes involved in cholesterol biosynthesis are indicative of the key role played by IGF1 in regulating the synthesis of cholesterol, the precursor for steroid hormones.

Insulin-like Growth Factor-1 and mTORC1 Signaling Promote the Intestinal Regenerative Response After Irradiation Injury.

Background & AimsIntestinal crypts have a remarkable capacity to regenerate after injury from loss of crypt base columnar (CBC) stem cells. After injury, facultative stem cells (FSCs) are activated to replenish the epithelium and replace lost CBCs. Our aim was to assess the role of insulin-like growth factor-1 (IGF-1) to activate FSCs for crypt repair.MethodsThe intestinal regenerative response was measured after whole body 12-Gy γ-irradiation of adult mice. IGF-1 signaling or its downstream effector mammalian target of rapamycin complex 1 (mTORC1) was inhibited by administering BMS-754807 or rapamycin, respectively. Mice with inducible Rptor gene deletion were studied to test the role of mTORC1 signaling in the intestinal epithelium. FSC activation post-irradiation was measured by lineage tracing.ResultsWe observed a coordinate increase in growth factor expression, including IGF-1, at 2 days post-irradiation, followed by a surge in mTORC1 activity during the regenerative phase of crypt repair at day 4. IGF-1 was localized to pericryptal mesenchymal cells, and IGF-1 receptor was broadly expressed in crypt progenitor cells. Inhibition of IGF-1 signaling via BMS-754807 treatment impaired crypt regeneration after 12-Gy irradiation, with no effect on homeostasis. Similarly, rapamycin inhibition of mTORC1 during the growth factor surge blunted the regenerative response. Analysis of Villin-CreERT2;Rptorfl/fl mice showed that epithelial mTORC1 signaling was essential for crypt regeneration. Lineage tracing from Bmi1-marked cells showed that rapamycin blocked FSC activation post-irradiation.ConclusionsOur study shows that IGF-1 signaling through mTORC1 drives crypt regeneration. We propose that IGF-1 release from pericryptal cells stimulates mTORC1 in FSCs to regenerate lost CBCs.

Adenovirus-Mediated Transduction of Insulin-Like Growth Factor 1 Protects Hippocampal Neurons from the Toxicity of Aβ Oligomers and Prevents Memory Loss in an Alzheimer Mouse Model.

Alzheimer's disease (AD) is the main cause of dementia in the elderly. Although activation of brain insulin signaling has been shown to be neuroprotective, to preserve memory in AD models, and appears beneficial in patients, the role of insulin-like growth factor 1 (IGF1) remains incompletely understood. We found reduced active/inactive IGF1 ratio and increased IGF1R expression in postmortem hippocampal tissue from AD patients, suggesting impaired brain IGF1 signaling in AD. Active/inactive IGF-1 ratio was also reduced in the brains of mouse models of AD. We next investigated the possible protective role of IGF1 in AD models. We used a recombinant adenoviral vector, RAd-IGF1, to drive the expression of IGF1 in primary hippocampal neuronal cultures prior to exposure to AβOs, toxins that accumulate in AD brains and have been implicated in early synapse dysfunction and memory impairment. Cultures transduced with RAd-IGF1 showed decreased binding of AβOs to neurons and were protected against AβO-induced neuronal oxidative stress and loss of dendritic spines. Significantly, in vivo transduction with RAd-IGF1 blocked memory impairment caused by intracerebroventricular (i.c.v.) infusion of AβOs in mice. Our results demonstrate altered active IGF1 and IGF1R levels in AD hippocampi, and suggest that boosting brain expression of IGF1 may comprise an approach to prevent neuronal damage and memory loss in AD.

The physiological role of growth hormone and insulin-like growth factors

The existence of insulin-like growth factors (IGFs) was recognized in connection with the stimulation of sulfate incorporation into cartilage. IGFs take part in the embryonal development and postnatal growth, in interaction with the growth hormone (GH). The physiological effects of IGF1 are promotion of tissue growth and development, stimulation of cell proliferation, effects on lipid and carbohydrate metabolism, anti-aging, anti-inflammatory, anabolic, anti-oxidant, neuro- and hepatoprotective properties. Our knowledge about the GH/IGF axis is diverse, partly contradictory, their research is continued intensively nowadays. We considered it worthwhile to review and interpret this information. Study on GH/IGF medical reports, with particular reference to the less known metabolic control. 75% of the growth factors are produced in the liver by GH and insulin stimulation; their effects are expressed on specific receptors, and modified by specific binding proteins. IGF1 directly increases the muscle mass, bone density, and the structure of the bones. Intestinal microbiota induces secretion of IGF1, which promotes the development and remodeling of the bones. Short-chain fatty acids, produced in microbial fermented fibers, induce secretion of IGF1, suggesting that microbial activity also affects bone health via IGF1. IGF1 also has a direct and indirect glucose-lowering effect, enhances free fatty acid oxidation in the muscle, reducing the flow of free fatty acid into the liver, improving insulin signaling, resulting in the reduction of hepatic glucose output, and improves insulin sensitivity. IGF1 directly influences the expression of circadian BMAL1 in hypothalamic cells: this refers to the newly recognized 'zeitgeber' role of IGF1. The bioactivity of insulin-like peptides in the brain is characterized by neuronal survival, excitatory and inhibitory neurotransmission, maintenance of normal free fatty acid levels, improvement of cognitive function, protection against cell damage, neurogenesis and angiogenesis. The effects of IGF2 are less outlined, however, it has a relevant role in the development of the fetus, and acts protectively on the brain. Lack or over-expression of IGF1 can be detected or may causally associated in many pathological conditions. According to these collected data, insulin sensitivity may be improved by different pathways. The role of IGFs in these processes should be a task of future research. Orv Hetil. 2019; 160(45): 1774-1783.

Loss of insulin-like growth factor-1 signaling in astrocytes disrupts glutamate handling.

Insulin-like Growth Factor-1 (IGF-1) has been studied extensively for its ability to promote neuronal growth and excitability. Declining levels of IGF-1 have been correlated with impaired learning and memory as well as an increased risk of neurodegenerative diseases. While neuronal regulation by IGF-1 is well understood, the role of IGF-1 in influencing astrocyte function requires further exploration. Astrocytes regulate many aspects of the brain microenvironment, including controlling glutamate-glutamine cycling, which ultimately supports neuronal metabolism, neurotransmission, and protection from over stimulation. In this study, we examined whether IGF-1 acts through its cognate receptor, IGFR, to alter astrocytic glutamate handling. We utilized both small molecule IGFR inhibitors and Cre-driven genetic approaches to reduce IGFR in vivo and in cultured rodent astrocytes. When IGFR was knocked out of primary astrocytes derived from igfrf/f mice using AAV5-CMV-Cre, significant reductions in glutamate uptake were observed. Similarly, inhibition of IGFR with picropodophyllotoxin for 2h, as well as 24h, reduced glutamate uptake in vitro. Mechanistically, short-term inhibition of IGFR resulted in a significant decrease in glutamate transporter availability on the cell surface, as assessed by biotinylation. Long-term inhibition of IGFR led to significant reductions in mRNA expression of glutamate transport machinery, as assessed with qPCR. Reduced glutamate transporter mRNA was also observed in the brains of astrocyte-specific IGFR-deficient mice, three to four months after knock-out was induced with tamoxifen. Interestingly, long-term IGF-1 inhibition also resulted in an increase in adenosine triphosphate-stimulated glutamate release, though no change in adenosine triphosphate-stimulated calcium flux was observed nor were any changes in purinergic receptor protein expression. Together, these data suggest that reduced IGF-1 signaling will favor an accumulation of extrasynaptic glutamate, which may contribute to neurodegeneration in disease states where IGF-1 levels are low. Cover Image for this issue: doi: 10.1111/jnc.14534.

Sevoflurane Affects Memory Through Impairing Insulin-Like Growth Factor Receptor Signaling.

Administration of sevoflurane (SEVO) may induce learning and memory deficits, which increases the chances of developing Alzheimer's disease. Here, we studied the effects of SEVO exposure on rats with a focus on the role of insulin-like growth factor (IGF) signaling. SEVO exposure significantly increased neuron cell apoptosis, and caused poor performance of the rats in behavior tests, by suppressing IGF-1 receptor (IGF1R). Bioinformatic analysis predicted microRNA(miR)-223-3p as an IGF1R-binding miRNA, the level of which increased in neurons after exposure to SEVO. In vitro, miR-223-3p suppressed the translation of IGF1R in neural cells. Moreover, transfection with antisense of miR-223-3p significantly attenuated SEVO exposure-induced neuron cell apoptosis. Taken together, these data suggest that SEVO-induced miR-223-3p upregulation suppresses IGF1R to impair IGF signaling, which subsequently leads to learning and memory impairments.

Insulin-like growth factor (IGF) signaling in T-cell acute lymphoblastic leukemia.

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive cancer, characterized by an uncontrolled expansion and accumulation of T-cell progenitors. During leukemic progression, immature T cells grow abnormally and occupy the bone marrow compartment, thereby interfering with the production of normal blood cells. Pediatric T-ALL is curable with intensive chemotherapy, but there are significant, long-term side effects and ~20% of patients suffer relapse for which there are limited treatment options. Adult T-ALL in contrast is largely incurable and refractory/relapsed disease is common despite multi-agent chemotherapy (5-year overall survival of ~40%), and thus new therapeutic targets are needed. We have reported previously on the role of insulin-like growth factor (IGF) signaling in T-ALL, and shown that it exerts potent phenotypes in both leukemia stem cell and bulk tumor cell populations. Modulators of IGF signaling may thus prove useful in improving outcomes in patients with T-ALL. In this review, we summarize the most recent findings relating to IGF signaling in T-ALL and outline therapeutic options using clinically relevant IGF signaling modulators.

Triple-Negative Breast Cancer: Current Understanding and Future Therapeutic Breakthrough Targeting Cancer Stemness.

Triple-negative breast cancer (TNBC) is cancer that tested as negative for estrogen receptors (ER), progesterone receptors (PR), and excess human epidermal growth factor receptor 2 (HER2) protein which accounts for 15%–20% of all breast cancer cases. TNBC is considered to be a poorer prognosis than other types of breast cancer, mainly because it involves more aggressive phenotypes that are similar to stem cell–like cancer cells (cancer stem cell, CSC). Thus, targeted treatment of TNBC remains a major challenge in clinical practice. This review article surveys the latest evidence concerning the role of genomic alteration in current TNBC treatment responses, current clinical trials and potential targeting sites, CSC and drug resistance, and potential strategies targeting CSCs in TNBC. Furthermore, the role of insulin-like growth factor 1 receptor (IGF-1R) and nicotinic acetylcholine receptors (nAChR) in stemness expression, chemoresistance, and metastasis in TNBC and their relevance to potential treatments are also discussed and highlighted.

The putative role of insulin-like growth factor (IGF)-binding protein 5 independent of IGF in the maintenance of pulpal homeostasis in mice.

Although insulin-like growth factor binding protein 5 (IGFBP5) may play a crucial role in activating the functions of periodontal and bone marrow stem cells, the factors responsible for regulating the maintenance of dental pulp stem cells (DPSCs) remain to be clarified. This study aimed to elucidate the role of IGFBP5 in maintaining pulpal homeostasis during tooth development and pulpal healing after tooth injury in doxycycline-inducible TetOP-histone 2B (H2B)-green fluorescent protein (GFP) transgenic mice (GFP expression was induced at E14.5 or E15.5) by using TUNEL assay, RT-PCR, in situ hybridization for Igfbp5, and immunohistochemistry for IGFBP5, Nestin, and GFP. To observe the pulpal response to exogenous stimuli, the roots of the maxillary first molars were resected, and the coronal portion was autografted into the sublingual region. Intense IGFBP5/Igfbp5 expression was observed in cells from the center of the pulp tissue and the subodontoblastic layer in developing teeth during postnatal Week 4. Intense H2B-GFP-expressing label-retaining cells (LRCs) were localized in the subodontoblastic layer in addition to the center of the pulp tissue, suggesting that slowly dividing cell populations reside in these areas. During postoperative days 3–7, the LRCs were maintained in the dental pulp, showed an IGFBP5-positve reaction in their nuclei, and lacked a TUNEL-positive reaction. In situ hybridization and RT-PCR analyses confirmed the expression of Igfbp5 in the dental pulp. These findings suggest that IGFBP5 play a pivotal role in regulating the survival and apoptosis of DPSCs during both tooth development and pulpal healing following tooth injury.

The Role of Insulin-Like Growth Factor-1 and Pregnancy-Associated Plasma Protein-A in Diagnosis of Acute Coronary Syndrome and Its Related Morbidities.

Introduction:Pregnancy-associated plasma protein-A (PAPP-A) is a metalloproteinase that plays a role in atherosclerotic plaque destabilization. In recent studies, insulin-like growth factor-1 (IGF-1) has been introduced as a mediator of atherosclerosis. PAPP-A and IGF-1 level may be important diagnostic indicators of acute coronary syndrome (ACS).Objective:The present study tried to assess the diagnostic role of IGF-1 and PAPP-A biomarkers in ACS spectrum.Methods:The serum level of IGF-1, PAPP-A and troponin I was determined in 121 consecutive patients with ACS. Relationships were assessed by t-test, ANOVA and the non-parametric equivalent. Accuracy of biomarkers was measured by the area under the ROC curve (AUC) and optimal cut-off points to diagnose STEMI and NSTEMI using Youden index.Results:In patients with acute ST segment elevation myocardial infarction (STEMI), all of these three biomarkers were significantly higher than those in patients with unstable angina (P= 0.028 for IGF-1, P<0.001 for PAPP-A and Troponin-I). Mean level of IGF-1 in patients with renal failure was significantly higher than that in patients without renal failure (137.9±35.1 vs 105.1±46.9, P=0.003), but PAPP-A and serum Troponin-I level had no significant difference in renal failure groups (P>0.05). ROC curve analysis showed that after Troponin-I, PAPP-A was a good discriminator between patients with STEMI and patients with unstable angina (AUC=0.79). Optimum cut-off value for PAPP-A was found to be 89.2 ng/ml, with sensitivity and specificity of 66.7% and 83.8%, respectively.Conclusion:PAPP-A can be a novel biomarker for both identification of patients with STEMI and risk stratification in patients with ACS.

The role of insulin-like growth factor 2 receptor-mediated homeobox gene expression in human placental apoptosis, and its implications in idiopathic fetal growth restriction.

Fetal growth restriction (FGR) is caused by poor placental development and function early in gestation. It is well known that placentas from women with FGR exhibit reduced cell growth, elevated levels of apoptosis and perturbed expression of the growth factors, cytokines and the homeobox gene family of transcription factors. Previous studies have reported that insulin-like growth factor-2 (IGF2) interacts with its receptor-2 (IGF2R) to regulate villous trophoblast survival and apoptosis. In this study, we hypothesized that human placental IGF2R-mediated homeobox gene expression is altered in FGR and contributes to abnormal trophoblast function. This study was designed to determine the association between IGF2R, homeobox gene expression and cell survival in pregnancies affected by FGR. Third trimester placentas were collected from FGR-affected pregnancies (n = 29) and gestation matched with control pregnancies (n = 30). Functional analyses were then performed in vitro using term placental explants (n = 4) and BeWo trophoblast cells. mRNA expression was determined by real-time PCR, while protein expression was examined by immunoblotting and immunohistochemistry. siRNA transfection was used to silence IGF2R expression in placental explants and the BeWo cell-line. cDNA arrays were used to screen for downstream targets of IGF2R, specifically homeobox gene transcription factors and apoptosis-related genes. Functional effects of silencing IGF2R were then verified by β-hCG ELISA, caspase activity assays and a real-time electrical cell-impedance assay for differentiation, apoptosis and cell growth potential, respectively. IGF2R expression was significantly decreased in placentas from pregnancies complicated by idiopathic FGR (P < 0.05 versus control). siRNA-mediated IGF2R knockdown in term placental explants and the trophoblast cell line BeWo resulted in altered expression of homeobox gene transcription factors, including increased expression of distal-less homeobox gene 5 (DLX5), and decreased expression of H2.0-Like Homeobox 1 (HLX) (P < 0.05 versus control). Knockdown of IGF2R transcription increased the expression and activity of caspase-6 and caspase-8 in placental explants, decreased BeWo proliferation and increased BeWo differentiation (all P < 0.05 compared to respective controls). This is the first study linking IGF2R placental expression with changes in the expression of homeobox genes that control cellular signalling pathways responsible for increased trophoblast cell apoptosis, which is a characteristic feature of FGR.

IGF-1/IGF-1R blockade ameliorates diabetic kidney disease through normalizing Snail1 expression in a mouse model.

This study investigated the role of insulin-like growth factor-1/insulin-like growth factor-1 receptor (IGF-1/IGF-1R) in the genesis and progression of diabetic kidney disease (DKD) in a streptozotocin (STZ)-induced mouse diabetes model. We showed elevated IGF-1 expression in the DKD kidneys after 16 wk of diabetic onset. Intraperitoneal administration of IGF-1R inhibitor (glycogen synthase kinase-3β, GSK4529) from week 8 to week 16 postdiabetes induction ameliorated urinary albumin excretion and kidney histological changes due to diabetes, including amelioration of glomerulomegaly, inflammatory infiltration, and tubulointerstitial fibrosis. The GSK4529 treatment also attenuated alterations in renal tubular expression of E-cad and matrix protein fibronectin. Moreover, renal fibrosis in DKD (without treatment) was associated with Snail1 overexpression that was effectively prevented by IGF-1R inhibition. Further experiments in cultured renal epithelial cells (NRK) showed that IGF-1 silencing reproduced in vivo effects of IGF-1R inhibition with markedly attenuated Snail1 expression and near normalization of the Ecad1 and fibronectin expression pattern. Further Snail1 silencing prevented high-glucose-induced changes without affecting IGF-1 expression, consistent with Snail1 acting downstream to IGF-1. The antifibrotic effects were also shown with benazepril or insulin treatment but to a much lesser degree. In summary, in STZ-induced diabetic mice, activation of IGF-1 in diabetic kidneys induces fibrogenesis through Snail1 upregulation. The diabetes-related histological and functional changes, as well as fibrogenesis, can be attenuated by IGF-1/IGF-1R inhibition.

IMP3 is a biomarker for non-muscle-invasive urothelial carcinoma of the bladder associated with an aggressive phenotype.

Bladder cancer is one of the most common malignancies of urinary tract. The current study aimed to investigate the role of insulin-like growth factor II messenger RNA binding protein 3 (IMP3) expression in the prognostic evaluation of non-muscle- invasive urothelial carcinoma of the bladder.Immunohistochemistry (IHC) was carried out to examine IMP3 protein expression in specimens from 183 cases of non-muscle-invasive urothelial carcinoma, 20 cases of muscle-invasive urothelial carcinoma and 20 benign tissues adjacent to cancer tissue.The expression of IMP3 was not detected in the adjacent benign tissues. The expression intensity of IMP3 in muscle-invasive samples was significantly higher than that in non-muscle-invasive urothelial carcinoma specimens (P = .008). IMP3 expression was significantly related with advanced tumor stage (P < .001), advanced tumor grade (P = .004), and tumor recurrence (P < .001) in non-muscle-invasive urothelial carcinomas. Kaplan–Meier analysis showed that IMP3-positive patients had much lower disease-free (P < .001), progression-free (P = .002) and metastasis-free (P = .019) survival rates compared with those with IMP3-negative tumors. By multivariable Cox analysis, we also found that IMP3 expression in non-muscle- invasive urothelial carcinomas proved to be an independent unfavorable prognostic factor of disease-free survival (HR: 2.52; 95% CI, 1.39–4.56; P = .002), progression- free survival (HR: 5.19; 95% CI, 1.54–17.46; P = .008) and metastasis-free survival (HR: 4.87; 95% CI, 1.08–22.02; P = .040).Our results demonstrate that the expression of IMP3 in non-muscle- invasive bladder cancer can serve as an independent predictor that will help recognize the subgroup of patients with a high ability to relapse, progress, and metastasize and who might get the maximum benefit from an early and more aggressive treatment strategy.

IGF1R Is a Potential New Therapeutic Target for HGNET-BCOR Brain Tumor Patients.

(1) Background: The high-grade neuroepithelial tumor of the central nervous system with BCOR alteration (HGNET-BCOR) is a highly malignant tumor. Preclinical models and molecular targets are urgently required for this cancer. Previous data suggest a potential role of insulin-like growth factor (IGF) signaling in HGNET-BCOR. (2) Methods: The primary HGNET-BCOR cells PhKh1 were characterized by western blot, copy number variation, and methylation analysis and by electron microscopy. The expression of IGF2 and IGF1R was assessed by qRT-PCR. The effect of chemotherapeutics and IGF1R inhibitors on PhKh1 proliferation was tested. The phosphorylation of IGF1R and downstream molecules was assessed by western blot. (3) Results: Phkh1 cells showed a DNA methylation profile compatible with the DNA methylation class “HGNET-BCOR” and morphologic features of cellular cannibalism. IGF2 and IGF1R were highly expressed by three HGNET-BCOR tumor samples and PhKh1 cells. PhKh1 cells were particularly sensitive to vincristine, vinblastine, actinomycin D (IC50 < 10 nM for all drugs), and ceritinib (IC50 = 310 nM). Ceritinib was able to abrogate the proliferation of PhKh1 cells and blocked the phosphorylation of IGF1R and AKT. (4) Conclusion: IGF1R is as an attractive target for the development of new therapy protocols for HGNET-BCOR patients, which may include ceritinib and vinblastine.

The complementary role of insulin-like growth factor II mRNA-binding protein 3 (IMP3) in diagnosis of Hodgkin's lymphoma

BackgroundHodgkin's Lymphoma (HL) is a peculiar subtype of lymphoid malignancies. The etiology of HL is still unknown. Insulin-like growth factor II mRNA-binding Protein 3 (IMP3) is a member of IMP family. In HL, IMP3 is expressed in the cytoplasmic compartment of the tumor cells (in both HRS cells & LP cells) against completely negative background of non-tumor cells except for residual germinal centers. Materials & MethodsOf 51 cases of Hodgkin's lymphoma (HL) referred to surgical pathology laboratory at oncology center, Mansoura University (OCMU), Egypt. All cases were stained for CD20, CD3, CD15, CD30 and IMP3. Regarding IMP3 antibody, The slides were then incubated with the Anti-IMP3, mouse monoclonal antibody (1:200, clone sc-365640, concentrated, California) that was used as primary antibody for IMP3 detection for 1 hour at room temperature, followed by incubation with the secondary antibody, poly HRP (horseradish peroxidase), conjugate for mouse/rabbit, for 20 minutes. ResultsIMP3 showed cytoplasmic immunoreactivity in 43 (83%) cases while 8 cases were negative. The sensitivity of combined CD30 & CD15, combined CD30 & IMP3, combined CD15 & IMP3 were 96%, 98% and 94% respectively. On the other hand, the sensitivity of CD30, CD15 and IMP3 alone were 92.2%, 68.6% and 84.3% respectively. All 23 studied cases of NSCHL, all the 17 cases of MCCHL, 7 out of 8 cases of LRCHL and the only case of LDCHL had predominant T-lymphocytes in their background. On the other hand, the 2 cases of NLPHL and only case of LRCHL had predominant B-lymphocytes in their background. ConclusionIMP3 is a novel marker that is expressed in large proportion of both types of HL against nearly negative background. It has no significant increase in sensitivity in detection of the tumor cells when combined with CD30. There are insignificant relations between IMP3 expression and different clinicopathological parameters. Further studies about IMP3 on a large scale of cases are required to confirm its mechanistic role in generation of HL.

Insulin-like growth factor 1 modulates the phosphorylation, expression, and activity of organic anion transporter 3 through protein kinase A signaling pathway

Organic anion transporter 3 (OAT3) plays a vital role in removing a broad variety of anionic drugs from kidney, thus avoiding their possible toxicity in the body. In the current study, we investigated the role of insulin-like growth factor 1 (IGF-1) in the regulation of OAT3. We showed that IGF-1 induced a dose- and time-dependent increase in OAT3 transport activity, which correlated well with an increase in OAT3 expression. The IGF-1-induced increase in OAT3 expression was blocked by protein kinase A (PKA) inhibitor H89. Moreover, IGF-1 induced an increase in OAT3 phosphorylation, which was also blocked by H89. These data suggest that the IGF-1 modulation of OAT3 occurred through PKA signaling pathway. To further confirm the involvement of PKA, we treated OAT3-expressing cells with PKA activator Bt2-cAMP, followed by examining OAT activity and phosphorylation. We showed that OAT3 activity and phosphorylation were much enhanced in Bt2-cAMP-treated cells as compared to that in control cells. Finally, linsitinib, an anticancer drug that blocks the IGF-1 receptor, abrogated IGF-1-stimulated OAT3 transport activity. In conclusion, our study demonstrated that IGF-1 regulates OAT3 expression and transport activity through PKA signaling pathway, possibly by phosphorylating the transporter.

Insulin-like growth factor-1 attenuates oxidative stress-induced hepatocyte premature senescence in liver fibrogenesis via regulating nuclear p53\u2013progerin interaction

Stress-induced premature senescence (SIPS), a state of cell growth arrest due to various stimuli, is implicated in the pathogeneses of hepatic fibrogenesis. Progerin, a permanently farnesylated mutant lamin A protein, likely leads to premature senescence to influent liver diseases. The previous reports showed that activation of insulin-like growth factor-1 (IGF-1) signaling could enhance cell longevity and attenuate liver fibrosis. However, the underlying mechanisms about hepatocyte premature senility in liver fibrosis, and how IGF-1 regulates cell premature aging and fibrogenesis, remain poorly understood. In the present study, we found the augment of hepatocyte oxidation and premature aging, along with the decrease of plasm IGF-1 level in patients with liver fibrosis and CCl4-induced liver injury rat models. Nevertheless, IGF-1 gene transfer to CCl4 rats to overexpress intrahepatic IGF-1 relieved hepatocyte oxidative stress and premature senescence, which was likely mediated by the p53/progerin pathway, to improve hepatic steatosis and fibrogenesis. In vitro, H2O2 caused abnormal accumulation of progerin in nuclear and activation of nuclear p53–progerin interaction to trigger primary rat hepatocyte premature senescence through the p21-independent pathway; while these effects were rescued by prolonged exogenous IGF-1 or the IGF-1 adenovirus vector. Furthermore, the IGF-1 adenovirus vector, transfected to H2O2-treated hepatocytes, reversed oxidative stress-induced premature senescence via enhancing cytoplasmic AKT1–p53 interaction and subsequently inhibiting nuclear p53–progerin interaction. Consequently, our data illuminate a novel role of IGF-1 in regulating stress-induced hepatocyte premature senescence in liver fibrosis: prolonged IGF-1 relieves oxidative stress-initiated hepatocyte premature senescence via inhibition of nuclear p53–progerin interaction to ameliorate hepatic steatosis and fibrogenesis.

Sitagliptin protects diabetic rats with acute myocardial infarction through induction of angiogenesis: role of IGF-1 and VEGF.

Angiogenesis is regulated in a tissue-specific manner in all patients, especially those with diabetes. In this study, we describe a novel molecular pathway of angiogenesis regulation in diabetic rats with myocardial infarction (MI) and examine the cardioprotective effects of different doses of sitagliptin. Male rats were divided into 5 groups: normal vehicle group, diabetic group, diabetic + MI, diabetic + MI + 5 mg/kg sitagliptin, and diabetic + MI + 10 mg/kg sitagliptin. Isoproterenol in diabetic rats resulted in significant (p < 0.05) disturbance to the electrocardiogram, cardiac histopathological manifestations, and an increase in inflammatory markers compared with the vehicle and diabetic groups. Treatment with sitagliptin improved the electrocardiogram and histopathological sections, upregulated vascular endothelial growth factor (VEGF) and transmembrane phosphoglycoprotein protein (CD34) in cardiac tissues, and increased serum insulin-like growth factor 1 (IGF-1) and decreased cardiac tissue homogenate for interleukin 6 (IL-6) and cyclooxygenase 2 (COX-2). A relationship was found between serum IGF-1 and cardiac VEGF and CD34 accompanied by an improvement in cardiac function of diabetic rats with MI. Therefore, the observed effects of sitagliptin occurred at least partly through an improvement in angiogenesis and the mitigation of inflammation. Consequently, these data suggest that sitagliptin may contribute, in a dose-dependent manner, to protection against acute MI in diabetic individuals.