Role Of IGF-I Research Articles

Association of IGF-1 and IGF-2 genotypes with respiratory muscle strength in individuals with COPD: A cross-sectional study.

Chronic obstructive pulmonary disease is a systemic disease characterized not only by respiratory symptoms but also by physical deconditioning and muscle weakness. One prominent manifestation of this disease is the decline in respiratory muscle strength. Previous studies have linked the genotypes of insulin-like growth factor 1 and 2 (IGF-1 and IGF-2) to muscle weakness in other populations without this disease. However, there is a notable knowledge gap regarding the biological mechanisms underlying respiratory muscle weakness, particularly the role of IGF-1 and IGF-2 genotypes in this pulmonary disease. Therefore, this study aimed to investigate, for the first time, the association between IGF-1 and IGF-2 genotypes with respiratory muscle strength in individuals with chronic obstructive pulmonary disease. In addition, we analyzed the relationship between oxidative stress, chronic inflammation, and vitamin D with respiratory muscle strength. A cross sectional study with 61 individuals with chronic obstructive pulmonary disease. Polymerase chain reaction of gene polymorphisms IGF-1 (rs35767) and IGF-2 (rs3213221) was analyzed. Other variables, related to oxidative stress, inflammation and Vitamin D were dosed from peripheral blood. Maximal inspiratory and expiratory pressure were measured. The genetic polymorphisms were associated with respiratory muscle strength ( 3.0 and 3.5; = 0.57). Specific genotypes of IGF-1 and IGF-2 presented lower maximal inspiratory and expiratory pressure (<0.05 for all). Oxidative stress, inflammatory biomarkers, and vitamin D were not associated with respiratory muscle strength. The polymorphisms of IGF-1 and IGF-2 displayed stronger correlations with respiratory muscle strength compared to blood biomarkers in patients with chronic obstructive pulmonary disease. Specific genotypes of IGF-1 and IGF-2 were associated with reduced respiratory muscle strength in this population.

The role of IGF-1 in exercise to improve obesity-related cognitive dysfunction.

Obesity is an important factor that threatens human health. The occurrence of many chronic diseases is related to obesity, and cognitive function decline often occurs with the onset of obesity. With the further prevalence of obesity, it is bound to lead to a wider range of cognitive dysfunction (ORCD). Therefore, it is crucial to suppress ORCD through intervention. In this regard, exercise has been shown to be effective in preventing obesity and improving cognitive function as a non-drug treatment. There is sufficient evidence that exercise has a regulatory effect on a growth factor closely related to cognitive function-insulin-like growth factor 1 (IGF-1). IGF-1 may be an important mediator in improving ORCD through exercise. This article reviews the effects of obesity and IGF-1 on cognitive function and the regulation of exercise on IGF-1. It analyzes the mechanism by which exercise can improve ORCD by regulating IGF-1. Overall, this review provides evidence from relevant animal studies and human studies, showing that exercise plays a role in improving ORCD. It emphasizes the importance of IGF-1, which helps to understand the health effects of exercise and promotes research on the treatment of ORCD.

CA 19-9 but Not IGF-1/IGFBP-2 Is a Useful Biomarker for Pancreatic Ductal Adenocarcinoma (PDAC) and Chronic Pancreatitis (CP) Differentiation.

There are still no effective diagnostic and prognostic biomarkers in pancreatic ductal adenocarcinoma (PDAC). The differentiation between PDAC and chronic pancreatitis (CP) is often challenging. The inflammatory mass in the course of CP causes diagnostic difficulties in differentiating them from neoplastic lesions and, thus, delays the initiation of radical treatment. Insulin-like growth factor 1 (IGF-1) and insulin-like growth factor-binding protein 2 (IGFBP-2) form a network involved in PDAC development. The role of IGFs in promoting pancreatic cancer cell proliferation, survival, and migration is well established, and their ability to stimulate tumor growth and metastasis is well documented. The aim of the study was to evaluate the usability of IGF-1, IGFBP-2, and IGF-1/IGFBP-2 ratio in PDAC and CP differentiation. The study included 137 patients: 89 patients with PDAC and 48 patients with CP. All subjects were tested for the levels of IGF-1 and IGFBP-2 using the ELISA method (Corgenix UK Ltd. R&D Systems), along with the level of CA 19-9 in serum. Additionally, the IGF-1/IGFBP-2 ratio was calculated. Further analyses used logit and probit models with varying determinants in order to discern between PDAC and CP patients. The models served as a basis for AUROC calculation. The mean IGF-1 serum level was equal to 52.12 ± 33.13 ng/mL in PDAC vs. 74.23 ± 48.98 ng/mL in CP (p = 0.0053). The mean level of IGFBP-2 was equal to 305.95 ± 194.58 ng/mL in PDAC vs. 485.43 ± 299 ng/mL in CP (p = 0.0002). The mean CA 19-9 serum concentration was 434.95 ± 419.98 U/mL in PDAC vs. 78.07 ± 182.36 U/mL in CP (p = 0.0000). The mean IGF-1/IGFBP-2 ratio was 0.213 ± 0.14 in PDAC vs. 0.277 ± 0.33 in CP (p = 0.1914). The diagnostic usefulness of indicators for the purpose of PDAC and CP differentiation was assessed by means of AUROC comparison. The AUROCs of IGF-1, IGFBP-2, and IGF-1/IGFBP-2 ratio ranged below 0.7, being lower than the AUROC of CA 19-9 (0.7953; 0.719 within 95% CI). Together, the CA 19-9 and IGFBP-2 AUROCs also ranged below 0.8. When age was included, the AUROC increased to 0.8632, and its 95% confidence interval held above the 0.8 limit. The sensitivity of the used markers was not correlated to the stage of pancreatic PDAC. The presented results indicate that CA 19-9 is a marker demonstrating high potential for PDAC and CP differentiation. The inclusion of additional variables into the model, such as the serum level of IGF-1 or IGFBP-2, slightly increased the sensitivity in differentiating CP from PDAC. The IGF-1/IGFBP-2 ratio turned out to be a good marker of pancreatic diseases, but insufficient for the purpose of CP and PDAC differentiation.

The role of IGF-1/GH in the aging process and the development of age-related diseases

One of the most important trends in geroscience is the search for the biomechanisms of aging and geroprotective methods. In recent years, more and more attention has been paid to the role of age-related decline in IGF-1 levels; processes that start with a decrease in the activity of the GH/IGF-1 axis. IGF-1 levels correlate differently with many age-associated diseases: diabetes mellitus, cancer, cardiovascular disease. A decrease in the level of IGF-1 and growth hormone in the elderly can contribute to the deterioration of the course of some pathologies, and also have a protective effect in the occurrence of different nosologies. The possibility of slowing down aging with the help of IGF-1 in basic research led to research aimed at studying the possibility of using IGF-1 preparations and growth hormone in clinical practice to slow down aging. We have studied the literature on the Pubmed platform, Scopus for the past 10 years in order to find some new information regarding influence of IGF-1 on aging, about the association between IGF-1 levels and major age-related diseases. We analyzed data of publications on the role of IGF-1 in aging and the development of age-related diseases. The search was carried out using key words: IGF-1, growth hormone, aging, the review included data from more than 60 publications.

Effect of chronic physiological stress on rat oocyte reserve: Role of IGF-1, AMH and Bcl-2

Effect of chronic physiological stress on rat oocyte reserve: Role of IGF-1, AMH and Bcl-2

Differential expression of some termite neuropeptides and insulin/IGF-related hormones and their plausible functions in growth, reproduction and caste determination.

Insulin-like growth factor (IGF) and other insulin-like peptides (ilps) are important hormones regulating growth and development in animals. Whereas most animals have a single female and male adult phenotype, in some insect species the same genome may lead to different final forms. Perhaps the best known example is the honeybee where females can either develop into queens or workers. More extreme forms of such polyphenism occur in termites, where queens, kings, workers and soldiers coexist. Both juvenile hormone and insulin-like peptides are known to regulate growth and reproduction as well as polyphenism. In termites the role of juvenile hormone in reproduction and the induction of the soldier caste is well known, but the role of IGF and other ilps in these processes remains largely unknown. Here the various termite ilps are identified and hypotheses regarding their functions suggested. Genome assemblies and transcriptome short read archives (SRAs) were used to identify insulin-like peptides and neuropeptides in termites and to determine their expression in different species, tissues and castes. Termites have seven different ilps, i.e. gonadulin, IGF and an ortholog of Drosophila insulin-like peptide 7 (dilp7), which are commonly present in insects, and four smaller peptides, that have collectively been called short IGF-related peptides (sirps) and individually atirpin, birpin, cirpin and brovirpin. Gonadulin is lost from the higher termites which have however amplified the brovirpin gene, of which they often have two or three paralogs. Based on differential expression of these genes it seems likely that IGF is a growth hormone and atirpin an autocrine tissue factor that is released when a tissue faces metabolic stress. Birpin seems to be responsible for growth and in the absence of juvenile hormone this may lead to reproductive adults or, when juvenile hormone is present, to soldiers. Brovirpin is expressed both by the brain and the ovary and likely stimulates vitellogenesis, while the function of cirpin is less clear.

AG1024, an IGF-1 receptor inhibitor, ameliorates renal injury in rats with diabetic nephropathy via the SOCS/JAK2/STAT pathway.

Insulin-like-growth factor-1 (IGF-1) is the ligand for insulin-like growth factor-1 receptor (IGF-1R), and the roles of IGF-1/IGF-1R in diabetic nephropathy (DN) are well-characterized previously. However, the biological functions of AG1024 (an IGF-1R inhibitor) in DN remain unknown. This study investigates the roles and related mechanisms of AG-1024 in DN. The experimental DN was established via intraperitoneal injection of streptozotocin, and STZ-induced diabetic rats were treated with AG1024 (20 mg/kg/day) for 8 weeks. The 24 h proteinuria, blood glucose level, serum creatinine, and blood urea nitrogen were measured for biochemical analyses. The increase in 24 h proteinuria, blood glucose level, serum creatinine, and blood urea of DN rats were conspicuously abated by AG1024. After biochemical analyses, the renal tissue specimens were collected, and as revealed by hematoxylin and eosin staining and Masson staining, AG-1024 mitigated typical renal damage and interstitial fibrosis in DN rats. Then, the anti-inflammatory effect of AG-1024 was assessed by western blotting and ELISA. Mechanistically, AG-1024 upregulated SOCS1 and SOCS3 expression and decreased phosphorylated JAK2, STAT1, and STAT3, as shown by western blotting. Collectively, AG-1024 (an IGF-1R inhibitor) ameliorates renal injury in experimental DN by attenuating renal inflammation and fibrosis via the SOCS/JAK2/STAT pathway.

Abstract C064: IGF-II regulates a critical mitochondrial protein, Magmas, with differential expression between African American and Non-Hispanic White women with TNBC

Abstract Breast cancer is the most common malignancy in women. Young African American (AA) women are affected by a higher incidence and mortality rate of triple-negative breast cancer (TNBC) compared to Non-Hispanic White (NHW) women. Currently, available treatment options are suboptimal, with a 5-year survival of less than 12% for metastatic TNBC. Our laboratory demonstrated that IGF-2 plays a pivotal role in the tumor aggressiveness of AA women. Moreover, tissues from AA women express high levels of IGF-2 and exhibit high activation of IGF-2 signaling pathways associated with tumorgenesis and chemoresistance. An emerging pathway linked to IGF-2 mediated chemoresistance and cell survival in TNBC is the regulation of mitochondrial and survival proteins. Mitochondrial Magmas is a mitochondrial protein found in all eukaryotic cells that is required for cell viability. It functions to transport nuclear proteins from the inner mitochondrial membrane to the mitochondrial matrix. Magmas can buffer increased reactive oxidative species (ROS) and promote survival of cancer cells. Overexpression of Magmas reduced ROS and enhanced cellular tolerance to oxidative stress; however, its downregulation raised cellular ROS and made cells more vulnerable to ROS-mediated death. Given the role of IGF-2 in regulating mitochondrial proteins, we investigated if IGF-2 regulated Magmas. We hypothesize that IGF-2 increases Magmas, and since AA women express higher levels of IGF-2, they will express higher Magmas levels. We used the CRL-2335 AA TNBC cell line and an IGF-2 knockdown of those same cells. Western blotting was used to detect the specific isoforms of IGF-2 and Magmas from cell lysates. Immunohistochemistry (IHC) characterized Magmas expression in paired, normal-tumor breast cancer tissues. Real time PCR was used to evaluate the expression of IGF2 and MAGMAS. The preliminary results showed that IGF-2 knockdown in CRL-2335 AA TNBC cells significantly decreased Magmas protein expression and its corresponding mRNA. In addition, tissue analysis demonstrated high levels of Magmas staining in TNBC tissue while little or no staining was detected in the normal tissues. Furthermore, tumor tissues of AA women showed significantly higher expression of Magmas as compared to tissues from NHW women. Targeting Magmas represents a novel and much needed tool to treat TNBC. Our team is currently validating Magmas as a target for Theranostics treatment, a promising emerging radiotherapy for TNBC patients. Citation Format: Jennifer D. Tran, Alfonso D. Duran, Qian-Wei Tan, Frankis G. Almaguel, Daisy De León. IGF-II regulates a critical mitochondrial protein, Magmas, with differential expression between African American and Non-Hispanic White women with TNBC [abstract]. In: Proceedings of the 15th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2022 Sep 16-19; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr C064.

IGF-Binding Proteins and Their Proteolysis as a Mechanism of Regulated IGF Release in the Nervous Tissue.

Insulin-like growth factors 1 and 2 (IGF-1 and IGF-2) play a key role in the maintenance of the nervous tissue viability. IGF-1 and IGF-2 exhibit the neuroprotective effects by stimulating migration and proliferation of nervous cells, activating cellular metabolism, inducing regeneration of damaged cells, and regulating various stages of prenatal and postnatal development of the nervous system. The availability of IGFs for the cells is controlled via their interaction with the IGF-binding proteins (IGFBPs) that inhibit their activity. On the contrary, the cleavage of IGFBPs by specific proteases leads to the IGF release and activation of its cellular effects. The viability of neurons in the nervous tissue is controlled by a complex system of trophic factors secreted by auxiliary glial cells. The main source of IGF for the neurons are astrocytes. IGFs can accumulate as an extracellular free ligand near the neuronal membranes as a result of proteolytic degradation of IGFBPs by proteases secreted by astrocytes. This mechanism promotes interaction of IGFs with their genuine receptors and triggers intracellular signaling cascades. Therefore, the release of IGF by proteolytic cleavage of IGFBPs is an important mechanism of neuronal protection. This review summarizes the published data on the role of IGFs and IGFBPs as the key players in the neuroprotective regulation with a special focus on the specific proteolysis of IGFBPs as a mechanism for the regulation of IGF bioavailability and viability of neurons.

Higher Prepubertal IGF-1 Concentrations Associate to Earlier Pubertal Tempo in Both Sexes

Introduction: Pubertal onset is triggered by multiple neuroendocrine interactions. The role of prepubertal IGF-1 in this process has not been explored in both sexes. Our objective was to analyze the association of prepubertal IGF-1 concentration with age at thelarche (B2) and menarche (M) in girls and age at gonadarche (G2) in boys. Methods: This is a longitudinal study (n = 1,196 boys and girls) within the Growth and Obesity Chilean Cohort Study (GOCS). At age ≈ 6.7 years, blood sample was taken for IGF-1. Subjects were divided into 4 groups according to the onset age of the pubertal event. Results: Higher prepubertal IGF-1 levels were observed at earlier ages of B2 (p = 0.003) and M onset (p = 0.041). A taller prepubertal height was observed at younger ages of B2 and M (p=<0.001 and 0.002, respectively). The hazard proportional regression models (HR) showed that with an increase of 1 SD in IGF-1, the HR of presenting B2 at younger ages was 1.25, and this association was maintained when adjusted for confounding variables. Similarly, the HR of presenting M at earlier ages was 1.21. This association was maintained only when adjusting for body mass index but not using further confounders. In boys, prepubertal IGF-1 showed a tendency to be significantly higher in children with earlier G2 and taller height (both p < 0.001). The HR of presenting G2 at younger ages was 1.22, and this association was maintained after adjusting for confounders. Conclusions: Higher IGF-1 levels in mid-childhood are associated with earlier puberty onset. The role of IGF-1 in the onset of puberty requires further investigation.

Abstract 191

Traditionally pharmacological Growth Hormone Stimulation Tests (GHSTs) have been used to distinguish true GHD from ISS and CDGP in pediatric endocrine clinics. However these tests are not physiological and subject the patients to unnecessary stress of multiple samplings and risk of hemodynamic instability. Various clinical and biochemical findings if studied appropriately can predict the need to perform GHSTs in such patients and minimize unnecessary testing. Aim: To study the role of IGF-1 levels as a predictor of and positive GHSTs in children and adolescents presenting with short stature (SS). Materials and Methods: Medical records of children and adolescents presenting with SS were retrieved and their demographic data, IGF-1 centiles and results of GHSTs were studied. A positive GHST was taken as peak GH level (&lt;7 ng/ml). Correlation of IGF-1 centile for chronological age and bone age with GHST results was studied and ROC curves were drawn to study the sensitivity and specificity of IGF-1 centiles in predicting positive GHST. Results: Data of 199 patients presenting with growth failure from 1st January 2010 to 31st March 2021 was collected. 65 females and 134 males were included. Mean age of the cohort was 11 years 4months and mean IGF-1 level was 132.8ng/ml. 166 patients had IGF-1 levels &lt; 30th centile for chronological age. The remainder 33 patients who had IGF-1 centiles &gt; 30th centile for chronological age consistently had negative GHST thus indicating unnecessary pharmacological testing. Conclusion: GHSTs can thus be avoided in children who have IGF-1 centile &gt;30th centile for chronological age and thus avoid unnecessary stress and risk to the patients.

Lessons from Laron Syndrome on the Role of IGF-I on Carbohydrate Metabolism

Laron syndrome (LS) is a rare form of dwarfism caused by defects in the growth hormone receptor causing congenital IGF-I deficiency. The effects of the IGF-I deficiency and its administration on the carbohydrate metabolism was studied in a cohort of 75 patients with LS. IGF-I deficiency in young children is accompanied by hypoglycemia, but progressive obesity leads to insulin resistance and glucose intolerance.

Role of IGF-1 in neuroinflammation and cognition deficits induced by sleep deprivation

Sleep deprivation negatively influences cognition, however, the regulatory mechanisms to counteract this effect have not been identified. IGF-1 has been shown to be anti-inflammatory and neuroprotective in CNS injury models. In this study, we determined the impact of IGF-1 on brain injury and inflammation while modeling sleep deprivation. We found that IGF-1 was downregulated in human peripheral blood and in mice subjected to sleep deprivation for 5 days, with reduced activation of the downstream PI3K/AKT/GSK-3β pathway in mice brains. In addition, we found reduced levels of the anti-apoptosis enzyme Bcl-2 and increased levels of pro-apoptosis enzyme Caspase-9 expression, together with increased pro-inflammatory factors. The administration of IGF-1 after sleep deprivation induced activation of the PI3K/AKT/GSK-3β pathway, reversed changes in Bcl-2, Caspase-9, and pro-inflammatory factors, and alleviated cognitive impairment. Notably, IGF-1 also induced activation of the PI3K/AKT/GSK-3β pathway, and displayed anti-apoptosis and anti-inflammatory properties under normal sleep conditions,while IGF-1 did not improve the cognition under normal sleep conditions. These results suggest that the IGF-1/PI3K/AKT/GSK-3β pathway is involved in the regulation of cognitive function after sleep deprivation through modulation of apoptosis and inflammatory response. IGF-1 could be a viable therapeutic target, though further investigation is required to better understand its role in sleep deprivation.

Overexpression of IGF-1 During Early Development Expands the Number of Mammary Stem Cells and Primes them for Transformation.

Insulin-like growth factor I (IGF-1) has been implicated in breast cancer due to its mitogenic and anti-apoptotic effects. Despite substantial research on the role of IGF-1 in tumor progression, the relationship of IGF-1 to tissue stem cells, particularly in mammary tissue, and the resulting tumor susceptibility has not been elucidated. Previous studies with the BK5.IGF-1 transgenic (Tg) mouse model reveals that IGF-1 does not act as a classical, post-carcinogen tumor promoter in the mammary gland. Pre-pubertal Tg mammary glands display increased numbers and enlarged sizes of terminal end buds, a niche for mammary stem cells (MaSCs). Here we show that MaSCs from both wild-type (WT) and Tg mice expressed IGF-1R and that overexpression of Tg IGF-1 increased numbers of MaSCs by undergoing symmetric division, resulting in an expansion of the MaSC and luminal progenitor (LP) compartments in pre-pubertal female mice. This expansion was maintained post-pubertally and validated by mammosphere assays in vitro and transplantation assays in vivo. The addition of recombinant IGF-1 promoted, and IGF-1R downstream inhibitors decreased mammosphere formation. Single-cell transcriptomic profiles generated from 2 related platforms reveal that IGF-1 stimulated quiescent MaSCs to enter the cell cycle and increased their expression of genes involved in proliferation, plasticity, tumorigenesis, invasion, and metastasis. This study identifies a novel, pro-tumorigenic mechanism, where IGF-1 increases the number of transformation-susceptible carcinogen targets during the early stages of mammary tissue development, and "primes" their gene expression profiles for transformation.

Role of IGF2 in the Study of Development and Evolution of Prostate Cancer.

Prostate Cancer (PC) is commonly known as one of the most frequent tumors among males. A significant problem of this tumor is that in early stages most of the cases course as indolent forms, so an active surveillance will anticipate the appearance of aggressive stages. One of the main strategies in medical and biomedical research is to find non-invasive biomarkers for improving monitoring and performing a more precise follow-up of diseases like PC. Here we report the relevant role of IGF2 and miR-93-5p as non-invasive biomarker for PC. This event could improve current medical strategies in PC.

Insulin-like growth factor 1 promotes neural differentiation of human stem cells from the apical papilla

ObjectiveInsulin-like growth factor 1 (IGF1) is one of the vital factors in regenerative endodontics. Previous studies have focused on the role of IGF1 in the mineralization of dental tissues. However, the role of IGF1 in the neural differentiation of dental stem cells was little discussed. DesignIGF1 was overexpressed in human stem cells from the apical papilla (hSCAPs) by lentivirus and knocked down in hSCAPs by small interfering RNA. The neural differentiation level of hSCAPs was investigated histologically by HE staining and Nissl staining after neural induction for 3 days. The expression of proteins was examined by western blot and immunofluorescence. ResultsIGF1 promoted neural differentiation of hSCAPs, more cell processes and Nissl-positive body stained cells. IGF1 overexpression could both promote glial differentiation in hSCAPs, characterized by the increase of S100β and GFAP proteins, and neuronal differentiation, characterized by the increase of βIII-tubulin and functional GAD67/vGLUT1 proteins. Conversely, IGF1 knockdown suppressed both glial and neuronal differentiation. IGF1 activated AKT to regulate the early neural differentiation of hSCAPs. ConclusionsThe results indicate IGF1 could promote neural differentiation of hSCAPs by activating AKT signaling and provide a cue for the candidate of induced neural seeding cells in regenerative endodontics.

Effects of Antidepressant Treatment on Neurotrophic Factors (BDNF and IGF-1) in Patients with Major Depressive Disorder (MDD).

Major depressive disorder (MDD) remains the subject of ongoing research as a multifactorial disease and a serious public health problem. There is a growing body of literature focusing on the role of neurotrophic factors in pathophysiology of MDD. A neurotrophic hypothesis of depression proposes that abnormalities of neurotrophins serum levels lead to neuronal atrophy and decreased neurogenesis, resulting in mood disorders. Consequently, in accordance with recent findings, antidepressant treatment modifies the serum levels of neurotrophins and thus leads to a clinical improvement of MDD. The purpose of this review is to summarize the available data on the effects of various antidepressants on serum levels of neurotrophins such as brain-derived neurotrophic factor (BDNF) and insulin-like growth factor (IGF-1). In addition, the authors discuss their role as prognostic factors for treatment response in MDD. A literature search was performed using the PubMed database. Following the inclusion and exclusion criteria, nine original articles and three meta-analyses were selected. The vast majority of studies have confirmed the effect of antidepressants on BDNF levels. Research on IGF-1 is limited and insufficient to describe the correlation between different antidepressant drugs and factor serum levels; however, four studies indicated a decrease in IGF-1 after treatment. Preliminary data suggest BDNF as a promising predictor of treatment response in MDD patients. The role of IGF-1 needs further investigation.

Growth Hormone/Insulin Growth Factor Axis in Sex Steroid Associated Disorders and Related Cancers.

To date, almost all solid malignancies have implicated insulin-like growth factor (IGF) signalling as a driver of tumour growth. However, the remarkable level of crosstalk between sex hormones, the IGF-1 receptor (IGF-1R) and its ligands IGF-1 and 2 in endocrine driven cancers is incompletely understood. Similar to the sex steroids, IGF signalling is essential in normal development as well as growth and tissue homoeostasis, and undergoes a steady decline with advancing age and increasing visceral adiposity. Interestingly, IGF-1 has been found to play a compensatory role for both estrogen receptor (ER) and androgen receptor (AR) by augmenting hormonal responses in the absence of, or where low levels of ligand are present. Furthermore, experimental, and epidemiological evidence supports a role for dysregulated IGF signalling in breast and prostate cancers. Insulin-like growth factor binding protein (IGFBP) molecules can regulate the bioavailability of IGF-1 and are frequently expressed in these hormonally regulated tissues. The link between age-related disease and the role of IGF-1 in the process of ageing and longevity has gained much attention over the last few decades, spurring the development of numerous IGF targeted therapies that have, to date, failed to deliver on their therapeutic potential. This review will provide an overview of the sexually dimorphic nature of IGF signalling in humans and how this is impacted by the reduction in sex steroids in mid-life. It will also explore the latest links with metabolic syndromes, hormonal imbalances associated with ageing and targeting of IGF signalling in endocrine-related tumour growth with an emphasis on post-menopausal breast cancer and the impact of the steroidal milieu.

Research progress of IGF-1 and cerebral ischemia.

Cerebral ischemic disease is a group of diseases that cause insufficient blood supply to the cerebrum, cerebellum or brain stem for different reasons, resulting in corresponding nervous system symptoms. Cardiovascular disease is the leading cause of death in the world. Among them, the death caused by cerebral ischemia accounts for the vast majority, and it is one of the fatal diseases in the middle-aged and elderly at present. Epidemiologic studies have projected increasing mortality due to cardiovascular disease worldwide (about 23.3 million people by 2030) because of the aging population. However, related studies have shown that insulin-like growth factor I (IGF-1) is a multifunctional cell proliferation regulator. It plays an important role in cerebral ischemia. It is effective in promoting cell differentiation, proliferation and individual development. Studies have shown that IGF-1 signaling pathway is a key pathway controlling cell growth and survival. There may be five mechanisms in cerebral ischemia: prevention of intracellular calcium overload, inhibition of the upregulation of nNOS, IGF-1upregulations activating HIF-1α, regulation of Bcl-2 to resist apoptosis, and enhancement of vascular endothelial function. Three critical nodes in the IGF-1 signaling pathway have been described in cardiomyocytes: protein kinase Akt/mammalian target of rapamycin (mTOR), Ras/Raf/extracellular signal-regulated kinase (ERK), and phospholipase C (PLC)/inositol 1,4,5-triphosphate (InsP3)/Ca2+. IGF-1 plays an important role in cerebral ischemia and myocardial ischemia, mainly by activating downstream of IGF-1, controlling cell death and differentiation or transcription work, improving the function of heart muscle cells, reducing the myocardial cell apoptosis induced by myocardial infarction, regulating endogenous protection and restoration of cerebral ischemia injury, thus protecting cerebral and myocardial injury. Related studies have shown that bcl-2 exerts great influence on both cerebral ischemia and myocardial ischemia. Therefore, the relevant pathways and targets of cerebral ischemia and myocardial ischemia and the role of IGF-1 in protecting the heart are reviewed in this paper.

Expression and functional role of IGFs during early pregnancy in placenta of water buffalo

Adequate vascularisation is a key factor for successful fetal development. We hypothesized that Insulin-Like Growth Factor (IGF) family members regulate angiogenesis along with promoting fetal development and growth. In this experiment, we determined the expression and functional role of IGF family in placental compartments (caruncle; CAR, cotyledon; COT) during different stages of early pregnancy in the water buffalo (Bubalus bubalis). Samples were collected from early pregnancy 1 (EP1, 28–45 days), early pregnancy 2 (EP2, 45–90 days), and third stage of estrous cycle (11–16 days), which was taken as control. In addition, the role of IGF1 on mRNA expression of vWF, StAR, CYP11A1, 3βHSD, PCNA, and BAX were elucidated in cultured trophoblast cells (TCC) obtained from EP2. Quantitative real-time PCR (q-PCR), westernblot, and immunohistochemistry were done to investigate the gene expression, protein expression, and localization of examined factors, and RIA was also done to assess progesterone (P4) concentration. Expression of IGFs, its receptors and binding proteins were found to be significantly higher (p < 0.05) in both CAR and COT as compared to control during early pregnancy, except binding proteins IGFBP1, 3 and 4 which were significantly (p < 0.05) downregulated in COT with advancement of pregnancy. mRNA expression was consistent with the findings of immunoblotting and immunolocalization experiments. Trophoblasts cell culture (TCC) study showed a significant time and dose-dependent effect of IGF1 onsteroidogenic transcript, which was found to be maximum at 100 ng/ml that paralleled with P4 accretion in the media (p < 0.05). Further, IGF1 upregulated the transcripts of vWF, PCNA, and downregulated BAX at the same concentration (p < 0.05). Overall, our results demonstrated that the expression of IGFs is a site-specific phenomenon in placentome, which indicates autocrine/paracrine and endocrine function. Our in-vitro finding support that IGF1 plays a critical role in placental development by promoting angiogenesis, steroid synthesis, and cell proliferation during early pregnancy.