Mini Review: Molecular Interpretation of the IGF/IGF-1R Axis in Cancer Treatment and Stem Cells-Based Therapy in Regenerative Medicine.

In addition to the fundamental role of insulin-like growth factor (IGF)/IGF-1 receptor (IGF-1R) signaling dysregulation in cancer initiation and proliferation, the IGF/IGF-1R signaling also plays an important role in the maintenance of stem cell characteristics and enhancement of stem cell-based therapeutic efficacy. This review focused on the role of IGF/IGF-1R signaling in preclinical IGF-targeted therapies, including IGF-1R monoclonal antibodies, IGF-1R tyrosine kinase inhibitors, and neutralizing antibodies of IGFs in multiple tumors and endocrine disorders. On the other hand, the function of IGF/IGF-1R signaling in stem cell self-renewal, pluripotency and therapeutic efficacy in regenerative medicine was outlined. Finally, the review summarized ongoing studies on IGF/IGF-1R signaling blockade in multiple cancers and highlighted the IGF-1R signaling modifications in stem cells as a potential strategy to improve stem cell-based therapeutics in regenerative medicine.

Effect of empagliflozin on circulating proteomics in heart failure: mechanistic insights into the EMPEROR programme.

AIMS: Sodium-glucose co-transporter 2 (SGLT2) inhibitors improve cardiovascular outcomes in diverse patient populations, but their mechanism of action requires further study. The aim is to explore the effect of empagliflozin on the circulating levels of intracellular proteins in patients with heart failure, using large-scale proteomics. METHODS AND RESULTS: Over 1250 circulating proteins were measured at baseline, Week 12, and Week 52 in 1134 patients from EMPEROR-Reduced and EMPEROR-Preserved, using the Olink® Explore 1536 platform. Statistical and bioinformatical analyses identified differentially expressed proteins (empagliflozin vs. placebo), which were then linked to demonstrated biological actions in the heart and kidneys. At Week 12, 32 of 1283 proteins fulfilled our threshold for being differentially expressed, i.e. their levels were changed by ≥10% with a false discovery rate <1% (empagliflozin vs. placebo). Among these, nine proteins demonstrated the largest treatment effect of empagliflozin: insulin-like growth factor-binding protein 1, transferrin receptor protein 1, carbonic anhydrase 2, erythropoietin, protein-glutamine gamma-glutamyltransferase 2, thymosin beta-10, U-type mitochondrial creatine kinase, insulin-like growth factor-binding protein 4, and adipocyte fatty acid-binding protein 4. The changes of the proteins from baseline to Week 52 were generally concordant with the changes from the baseline to Week 12, except empagliflozin reduced levels of kidney injury molecule-1 by ≥10% at Week 52, but not at Week 12. The most common biological action of differentially expressed proteins appeared to be the promotion of autophagic flux in the heart, kidney or endothelium, a feature of 6 proteins. Other effects of differentially expressed proteins on the heart included the reduction of oxidative stress, inhibition of inflammation and fibrosis, and the enhancement of mitochondrial health and energy, repair, and regenerative capacity. The actions of differentially expressed proteins in the kidney involved promotion of autophagy, integrity and regeneration, suppression of renal inflammation and fibrosis, and modulation of renal tubular sodium reabsorption. CONCLUSIONS: Changes in circulating protein levels in patients with heart failure are consistent with the findings of experimental studies that have shown that the effects of SGLT2 inhibitors are likely related to actions on the heart and kidney to promote autophagic flux, nutrient deprivation signalling and transmembrane sodium transport.

IGF family effects on development, stability, and treatment of hematological malignancies.

Multiple factors, including growth factors, are shown to be culprits of cancer outset and persistence. Among growth factors, insulin-like growth factors (IGFs) family are of more importance in the prognosis of blood malignancies. After binding to their corresponding receptor, IGFs initiate PI3K/AKT signaling pathway and increase the translation of intracellular proteins, such as cell division-related proteins. They also stimulate the transcription of cell division-related genes using the Ras-GTP pathway. In addition to organs such as the liver, IGFs are secreted by tumor cells and can cause growth and proliferation of self or tumor cells via autocrine and paracrine methods. Current studies indicate that decreasing the effects of IGF by blocking them, their receptors, or PI3K/AKT pathway using various drugs could help to suppress the division of tumor cells. Here, we delineate the role of the IGF family in hematologic malignancies and their potential mechanisms.

Insulin-Like Growth Factors in the Pathogenesis of Neurological Diseases in Children.

Insulin-like growth factors play a key role for neuronal growth, differentiation, the survival of neurons and synaptic formation. The action of IGF-1 is most pronounced in the developing brain. In this paper we will try to give an answer to the following questions: Why are studies in children important? What clinical studies in neonatal asphyxia, infantile spasms, progressive encephalopathy-hypsarrhythmia-optical atrophy (PEHO) syndrome, infantile ceroid lipofuscinosis (INCL), autistic spectrum disorders (ASD) and subacute sclerosing encephalopathy (SSPE) have been carried out? What are IGF-based therapeutic strategies? What are the therapeutic approaches? We conclude that there are now great hopes for the therapeutic use of IGF-1 for some neurological disorders (particularly ASD).

Study of modified electroconvulsive therapy combined with risperidone oral solution in the treatment of agitation in the acute stage of epilepsy and expression level changes of insulin-like growth factor-1.

BACKGROUND: The aim of this paper was to explore the efficacy of modified electroconvulsive therapy (MECT) combined with risperidone oral solution in the treatment of agitation in the acute stage of epilepsy, and the effects of insulin-like growth factor-1 mRNA and protein expression. METHODS: Forty-six cases with seizures and agitation in the acute stage were included from February 2012 to February 2014. This study was approved by the ethics committee in our hospital. Patients were divided randomly into the experimental (23 cases) and control (23 cases) groups. The patients in the experimental group were treated with MECT combined with risperidone oral solution. The patients in the control group were treated with risperidone oral solution. The Positive and Negative Symptom Scale (PANSS) score and Treatment-Emergent Symptom Scale (TESS) score were compared before and after treatment. The insulin-like growth factor-1 (IGF-1) protein and mRNA expression level were detected with enzyme-linked immunosorbent assay (ELISA) and qRT-PCR, respectively. RESULTS: There were no significant differences on positive and negative symptom scores or total score in the two groups before treatment (P>0.05). After treatment, the positive symptom score, negative symptom score, and total score all decreased in both groups, and the decrease was more obvious in the experimental group (P<0.05). After treatment, TESS scores of the experimental group were significantly lower than those of the control group (P<0.05). In the experimental group, the total efficiency was significantly higher than that in the control group (P<0.05). Before treatment, there were no significant differences in the expression levels of IGF-1 protein or mRNA in the two groups (P>0.05), while after treatment the expression levels of IGF-1 protein and mRNA decreased in both groups. However, the decrease was more obvious in the experimental group. The differences were all significant for scores (P<0.05). CONCLUSIONS: The combined application of MECT and risperidone oral solution in the treatment of agitation can improve the clinical efficacy to some extent.

[A remedy against obesity? The role of lactoferrin in the metabolism of glucose and lipids]. / Zloty srodek na otylosc? Udzial laktoferryny w metabolizmie glukozy i lipidów.

Obesity, dyslipidemia, hyperglycemia/type II diabetes and hypertension together constitute the so-called metabolic syndrome. Frequency of occurrence of these serious metabolic disturbances is associated with life style and is on the rise in prosperous industrialized countries. These diseases represent not only a serious health problem but also social and economic ones, and involve in prophylaxis and treatment various specialists (physicians, dieticians and psychologists). For about two decades research has been conducted on the possibility to apply milk-derived proteins in prevention and treatment of the above mentioned metabolic diseases. Lactoferrin (LF), a protein present in milk and excretory fluids of mammals, is one of the most intensively studied milk proteins for therapeutic application. Initial trials revealing an advantageous effect of LF on lipid metabolism and obesity enrolled only a few volunteers and were performed in Japan in 2003. Subsequent trials were conducted on animals as well as in clinics, and the positive results were supported by in vitro tests. After oral administration of LF, decreases of body weight, waist measurement, visceral fat tissue, plasma and liver fatty acid concentrations, triglycerides and cholesterol were registered. The mechanism of LF action may involve several processes, such as inhibition of adipogenesis, decrease of dietary triglyceride absorption, elevation of HDL cholesterol possessing anti-atherogenic properties, inhibition of accumulation of oxidized LDL cholesterol forms in macrophages and protection against formation of foam cells. LF also increases the susceptibility of cells to insulin action, including in conditions when the response to insulin is lowered (during inflammation). In addition, LF regulates activity of insulin-like growth factor (IGF). The data collected to date indicate that LF is a promising, completely nontoxic, natural remedy which (as for example a food supplement) may be applied in long-term prophylaxis and therapy of metabolic disturbances, such as dyslipidemia, obesity and insulin resistance/type II diabetes. 

The insulin-like growth factors and growth disorders of childhood.

Specific lesions of the growth hormone (GH)/insulin-like growth factor (IGF) axis have been identified in humans, each of which has distinctive auxologic and biochemical features. Measures of circulating IGF-I are useful in diagnosing growth disorders in childhood and in evaluating response to GH therapy. Recombinant human IGF-I is an effective treatment of severe primary IGF deficiency, which is typical of patients with GH receptor defects (Laron syndrome). Such treatment has been limited to a few severely affected patients. Future studies will provide new insight into IGF-I as treatment and into the nature of growth disorders that involve the IGF axis.

The insulin-like growth factor system in bone: basic and clinical implications.

The insulin-like growth factor (IGF) regulatory system is critical for skeletal growth and maintenance. Initially there was great hope that the recombinant IGFs might be used clinically for disorders ranging from short stature to fracture repair and osteoporosis. Although this potential was not realized, basic and translational studies have continued, providing significant insights into the role of this family of growth factors in skeletal homeostasis and the pathophysiology of several bone disorders. This article reviews the importance of the IGF regulatory system in skeletal growth and maintenance.

Insulin-like growth factors in normal and diseased kidney.

This article reviews the physiology of the insulin-like growth factor (IGF) system in the kidney and the changes and potential role of this system in selected renal diseases. The potential therapeutic uses of recombinant human IGF-I for the treatment of acute and chronic kidney failure are briefly discussed.

Insulin-like growth factors in the peripheral nervous system.

Insulin-like growth factors (IGFs) play an integral role in development, growth, and survival. This article details the current understanding of the effects of IGFs in the peripheral nervous system (PNS) during health and disease, and introduces how the IGF system regulates PNS development and impacts growth and survival of PNS cells. Also discussed are implications of IGF signaling in neurodegeneration and the status and prospects of IGF therapies for PNS conditions. There is substantial support for the application of IGF therapies in the treatment of PNS injury and disease.

Retinopathy of prematurity promising newer modalities of treatment.

Retinopathy of prematurity (ROP) is a disorder of neonatal retinal vascularization. The incidence is increasing in developing countries like India in view of the rising numbers of preterm deliveries and improved neonatal care. Traditional modalities of treatment included cryotherapy and laser therapy, which were laborious and required special training. Hence, research is on way to find novel treatment modalities directed at various levels of pathogenesis for this blinding disease. We reviewed the published and unpublished literature on newer methods of ROP management. The pathogenesis of ROP has been studied with respect to the mediators of angiogenesis. Anti vascular endothelial growth factor (Anti-VEGF) therapy has been extensively studied and the studies have demonstrated its promising role early stages of ROP. The role of Insulin like growth factor (IGF), Granulocyte colony stimulating factor (GCSF), and June kinases (JNK) inhibitors are being studied by various researchers across the world. Gene therapy holds promise in the reversal of ROP changes.

Structural basis for therapeutic intervention of uPA/uPAR system.

Urokinase-type plasminogen activator (uPA) is one of the two physiological serine proteases responsible for the activation of plasminongen to plasmin. uPA activity is regulated by its inhibitors (PAI-1 and PAI-2) and its receptor (uPAR), and an expanding list of their interacting proteins. In addition to plasminogen activation, this system also plays important roles in the regulation of many cellular processes including cell proliferation, adhesion and migration. It is beyond reasonable doubt that this enzyme system plays a central role in tumor biology and represents a high potential target for therapeutic intervention of tumor growth and metastasis. During the past fifteen years, crystal structures of uPA and its inhibitors have facilitated the development of uPA inhibitors. Many crystal structures of proteins in the uPA/uPAR system have also been reported recently, especially a series of structures of uPAR and its complexes with vitronectin and uPA, facilitating the development and evaluation of uPAR inhibitors. Recent progress on uPA inhibitors will be summarized in this article. The unique structural features and the druggable potentials of these new structures will also be discussed.

Variable degree of growth hormone (GH) and insulin-like growth factor (IGF) sensitivity in children with idiopathic short stature compared with GH-deficient patients: evidence from an IGF-based dosing study of short children.

CONTEXT: We recently showed that, in IGF-based GH therapy, the IGF-I target chosen affects GH dose requirements, and higher IGF-I targets are associated with more robust growth parameters. OBJECTIVE: The objective of the study was to compare the response of GH-deficient (GHD) vs. idiopathic short-stature (ISS) children to IGF-based GH therapy. DESIGN: This was a 2-yr, open-label, randomized trial. SETTING: The setting was multicenter and outpatient. PATIENTS: Prepubertal short children [height sd score (SDS) < -2] with low IGF-I levels (or= 7 ng/ml). INTERVENTIONS: Patients were randomized 2:2:1 to three treatment groups: IGF-I target of 0 SDS (IGF0T), 2 SDS (IGF2T), or a conventional weight-based GH dosing of 40 microg/kg x d (Conv). MAIN OUTCOME MEASURES: Change in (Delta) height SDS, IGF-I SDS, and GH dose was measured. RESULTS: ISS subjects required higher GH doses than GHD patients in the IGF2T (but not IGF0T) arm (medians 119 and 65 microg/kg x d, respectively), indicating that ISS represents a partial GH-insensitive state that manifests during treatment with higher doses of GH. GHD children grew more than those with ISS in both IGF-targeted dosage groups despite similar IGF-I levels (suggesting a degree of IGF insensitivity in ISS subjects): Delta height SDS of 2.04 +/- 0.17 for GHD and 1.33 +/- 0.09 for ISS groups in IGF2T, 1.41 +/- 0.13 for children with GHD, and 0.84 +/- 0.07 for those with ISS in IGF0T. CONCLUSION: IGF-based GH dosing is clinically feasible in both GHD and ISS patients, although GH dose requirements and auxological outcomes are distinct between these groups. This suggests a degree of both GH and IGF insensitivity in subjects with ISS that requires specific management strategies to optimize growth during GH therapy.

Growth factors: possible roles for clinical management of the short bowel syndrome.

The structural and functional changes during intestinal adaptation are necessary to compensate for the sudden loss of digestive and absorptive capacity after massive intestinal resection. When the adaptive response is inadequate, short bowel syndrome (SBS) ensues and patients are left with the requirement for parenteral nutrition and its associated morbidities. Several hormones have been studied as potential enhancers of the adaptation process. The effects of growth hormone, insulin-like growth factor-1, epidermal growth factor, and glucagon-like peptide 2 on adaptation have been studied extensively in animal models. In addition, growth hormone and glucagon-like peptide 2 have shown promise for the treatment of SBS in clinical trials in human beings. Several lesser studied hormones, including leptin, corticosteroids, thyroxine, testosterone, and estradiol, are also discussed.

Talla baja idiopática (TBI): estado actual / Idiopathic short stature (ISS): current status

El diagnóstico de talla baja idiopática (TBI) se fundamenta en el desconocimiento de la causa que origina el que un niño o adolescente presente talla baja inferior a -2 DE para su edad y sexo, referido a su población. Se trata de una entidad nosológica heterogénea, cuyo diagnóstico se debe a la exclusión de las causas conocidas que determinara una afectación del crecimiento físico. En un término descriptivo, y arbitrario que únicamente puede emplearse cuando un niño presenta talla baja para la población y sexo del que procede y, la historia clínica, el examen físico y los estudios complementarios no demuestran ninguna causa responsable. Más específicamente, podría afirmarse que en un paciente catalogado de talla baja idiopática, la secreción de GH es normal, no existen antecedentes de haber sido pequeño para la edad gestacional, las proporciones corporales son normales, no existe patología orgánica, se han descartado entidades sindrómicas que cursan con talla baja y no se detecta ninguna patología psiquiátrica de base. Por consiguiente, el término TBI no se basa en ningún hallazgo positivo, sino en la exclusión de la patología orgánica, sindrómica, mental y molecular conocidas. Asistimos, por tanto aun complejo diagnóstico que requiere investigar múltiples causas, un auténtico tratado de medicina interna de la infancia, para poder afirmar que la etiología de la talla baja es realmente idiopática para nuestros conocimientos actuales. Los progresos efectuados en el diagnóstico molecular de nuevas enfermedades monogénicas, tanto en pacientes con talla baja armónica como disarmónica, están siendo extraordinarios en los últimos años y su contribución al esclarecimiento de las bases moleculares de la talla baja idiopática, está siendo ciertamente relevante. Los progresos en los consensos internacionales están siendo fructíferos, analizando las bases diagnósticas y terapéuticas. El tratamiento con hormona de crecimiento biosintética de los pacientes con talla baja idiopática, aunque aprobado por la FDA, resta por dilucidarse; muy en particular, los casos que pudieran requerir tratamiento con hormona de crecimiento o con factor de crecimiento semejante a la insulina tipo I, o simplemente observación de su evolución auxológica sin terapia. El empleo de inhibidores de aromatasa, puede ser de utilidad para algunos niños, El tratamiento con análogos de GnRH en combinación con GH al inicio de la pubertad puede, asimismo, ser beneficioso para el paciente (AU)

The diagnosis of idiopathic short stature (ISS) indicates that the cause of the child or adolescent´s short stature is unknown. This is a nosologically heterogeneous condition that is fundamentally diagnosed by excluding all known circumstances that affect lineal growth. It is an arbitrary and descriptive term that can only he employed when the child presents with short stature for age and sex for their population of origin and the cal history, physical exam and complementary studies do not demonstrate any plausible cause. More specifically, in a patient cataloged as having ISS, GH secretion is normal, there is no indication of having been small is not organic pathology present, all syndromes that are associated with short stature have been discarded, and there is no underlying psychiatric pathology. Hence, the term idiopathic short stature is not based on any positive finding, only the exclusion of known organic, syndromic, mental and molecular pathologies. Therefore, we are confronted with a complex diagnosis that requires the study of multiple organic, syndromic and molecular causes, an authentic textbook of internal medicine, in order to confirm that the etiology of the short stature is really idiopathic based on our current knowledge. The progress made in the molecular diagnosis of new monogenic diseases, in patients with harmonic short stature as well as disharmonic, has been extraordinary in recent years. This has made a very important contribution to the understanding of the molecular basis of idiopathic short stature. The progress in international consensus has also been very fruitful, including the analysis of the requirements for diagnosis and therapy. Treatment with biosynthetic growth hormone of patients with idiopathic short stature, although approved by the FDA, remains to be clarified, especially in cases requiring treatment with recombinant growth hormone of patients with idiopathic short stature, although approved by the FDA, remains to be clarified, especially in cases requiring treatment with recombinant growth hormone or insulin-like growth factor I, or will require auxological observation without therapy. Aromatase inhibitors could be of interest for some boys. Treatment with GnRH analogues in combination with GH at the start of puberty could benefit some patients (AU)

The insulin-like growth factor system as a potential therapeutic target in gastrointestinal stromal tumors.

The majority of gastrointestinal stromal tumors (GISTs) are characterized by oncogenic gain-of-function mutations in the receptor tyrosine kinase (RTK) c-KIT with a minority in PDGFRalpha. Therapy for GISTs has been revolutionized by the use of the selective tyrosine kinase inhibitor imatinib mesylate (IM). For the subset (approximately 10-15%) of GISTs that lack oncogenic mutations in these receptors, the genetic changes driving tumorigenesis are unknown. We recently reported that the gene encoding the insulin-like growth factor 1 receptor (IGF-1R) is amplified in a subset of GISTs, and the IGF-1R protein is overexpressed in wild-type and pediatric GISTs. In this report we present a more complete picture of the involvement of components of the insulin-like growth factor-signaling pathway in the pathogenesis of GISTs. We also discuss how the IGF pathway may provide additional molecular targets for the treatment of GISTs that respond poorly to IM therapy.

Insulin-like growth factor system regulates oligodendroglial cell behavior: therapeutic potential in CNS.

Amongst the many soluble extracellular factors stimulating intracellular signal transduction pathways and driving cellular processes such as proliferation, differentiation and survival, insulin-like growth factors (IGFs) stand out as indispensable factors for proper oligodendrocyte differentiation and accompanying myelin production. Owing to its potent myelinogenic capacity and its neuroprotective properties, IGFs hold therapeutic potential in demyelinating and neurodengenerative diseases. However, the IGF system is comprised of a complex molecular network involving regulatory binding proteins, proteases, cell surface and extracellular matrix components which orchestrate IGF-specific functions. Thus, the complexity by which these factors are tightly regulated makes a simplistic therapeutic approach towards treating demyelinating conditions unfeasible. In the present review, we address these issues and consider current therapeutic prospects of oligodendrocyte-targeted IGF-based therapies.