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Context Prader-Willi syndrome (PWS) is associated with impaired growth hormone (GH) secretion and decreased insulin-like growth factor (IGF)-I levels. Pappalysins (PAPP-A, PAPP-A2) and stanniocalcins (STC-1, STC-2) regulate IGF binding-protein (IGFBP) cleavage and IGF bioavailability, but their implication in PWS is unknown. Objective We determined serum levels of PAPP-As and STCs in association with IGF axis components in prepubertal and pubertal patients with PWS, also analyzing the effect of GH treatment. Methods Forty children and adolescents with PWS and 120 sex- and age-matched controls were included. The effect of GH was evaluated at 6 months of treatment in 11 children. Results Children with PWS had lower levels of total IGF-I, total and intact IGFBP-3, acid-labile subunit, intact IGFBP-4, and STC-1, and they had higher concentrations of free IGF-I, IGFBP-5, and PAPP-A. Patients with PWS after pubertal onset had decreased total IGF-I, total and intact IGFBP-3, and intact IGFBP-4 levels, and had increased total IGFBP-4, and STCs concentrations. GH treatment increased total IGF-I, total and intact IGFBP-3, and intact IGFBP-4, with no changes in PAPP-As, STCs, and free IGF-I levels. Standardized height correlated directly with intact IGFBP-3 and inversely with PAPP-As and the free/total IGF-I ratio. Conclusion The increase in PAPP-A could be involved in increased IGFBP proteolysis, promoting IGF-I bioavailability in children with PWS. Further studies are needed to establish the relationship between growth, GH resistance, and changes in the IGF axis during development and after GH treatment in these patients. [ABSTRACT FROM AUTHOR]

Simple Summary: In dairy cows, a hormone called insulin-like growth factor 1 (IGF-1) helps to control growth and reproduction. It affects how oocytes develop in the ovaries. IGF-1 is usually attached to binding proteins (IGFBPs), which can limit its effects. This study looked at how IGF-1 transfers between blood and the fluid around the oocyte. We checked IGF-1 and protein levels in both places and also measured energy levels using ketones. We examined gene activity in ovary cells too to look for local regulation. We found that IGF-1 levels in blood and ovarian fluid are related. High ketone levels, which indicate low energy, were linked to lower IGF-1 and some of the IGFBP. Some gene activity is also related to IGF-1 levels. In summary, while additional research is necessary to fully understand the local regulatory mechanisms, our findings suggest that the transfer of IGF-1 between systems may link metabolic issues to fertility challenges in dairy cows. Insulin-like growth factor 1 (IGF-1) regulates dairy cow reproduction, while the paracrine IGF system locally influences fertility. In both systems, IGF-1 bioactivity is regulated through binding proteins (IGFBPs) inhibiting IGF-1 binding to its receptor (IGF1R). This study aimed to investigate a possible transfer between this endocrine and paracrine system. Therefore, blood and follicular fluid (FF) from postpartum dairy cows were analysed for ß-hydroxybutyrate (BHB), IGF-1, IGFBP-2, -3, -4, -5, and an IGFBP fragment in two study parts. The mRNA expression of IGFBP-2, IGFBP-4, IGF1R, and the pregnancy-associated plasma protein A (PAPP-A) in granulosa cells was measured. The results showed correlations between plasma and FF for IGF-1 (r = 0.57, p < 0.001) and IGFBP-2 (r = −0.57, p < 0.05). Blood BHB negatively correlated with IGF-1 in blood and FF and IGFBP-3, -5 and total IGFBP in blood (IGF-1 plasma: r = −0.26, p < 0.05; FF: r = −0.35, p < 0.05; IGFBP-3: r = −0.64, p = 0.006; IGFBP-5: r = −0.49, p < 0.05; total IGFBP: r = −0.52, p < 0.05). A negative correlation was found between IGFBP-2 expression and IGF-1 concentration in FF (r = −0.97, p = 0.001), while an IGFBP fragment positively correlated with IGF1R-mRNA in FF (r = 0.82, p = 0.042). These findings suggest a transfer and local regulation between the somatotropic axis and the follicular IGF system, linking the metabolic status with local effects on dairy cow fertility. [ABSTRACT FROM AUTHOR]

Context Anomalies in the growth hormone (GH)/insulin-like growth factor (IGF) axis, are common in children with type 1 diabetes mellitus (T1DM), even in those reaching a normal or near-normal final height. However, concentrations of the IGF bioavailability regulatory factors (pappalysins [PAPP-As] and stanniocalcins [STCs]) have not been reported in children with T1DM. Objective To determine serum concentrations of PAPP-As and STCs in children at diagnosis of T1DM and after insulin treatment and the correlation of these factors with other members of the GH/IGF axis, beta-cell insulin reserve, auxology, and nutritional status. Methods A single-center prospective observational study including 47 patients (59.5% male), with T1DM onset at median age of 9.2 years (interquartile range: 6.3, 11.9) was performed. Blood and anthropometric data were collected at diagnosis and after 6 and 12 months of treatment. Results At 6 and 12 months after T1DM diagnosis, there was improvement in the metabolic control (decrease in glycated hemoglobin [HbA1c] at 12 months −3.66 [95% CI: −4.81, −2.05], P =.001), as well as in body mass index SD and height SD (not statistically significant). STC2 increased (P <.001) and PAPP-A2 decreased (P <.001) at 6 and 12 months of treatment onset (P <.001), which was concurrent with increased total IGF-I and IGF-binding protein concentrations, with no significant modification in free IGF-I concentrations. HbA1c correlated with PAPP-A2 (r = +0.41; P <.05) and STC2 (r = −0.32; P <.05). Conclusion Implementation of insulin treatment after T1DM onset modifies various components of the circulating IGF system, including PAPP-A2 and STC2. How these modifications modulate linear growth remains unknown. [ABSTRACT FROM AUTHOR]

Abstract Cells that are exposed to harmful genetic damage, either from internal or external sources, may undergo senescence if they are unable to repair their DNA. Senescence, characterized by a state of irreversible growth arrest, can spread to neighboring cells through a process known as the senescence-associated secretory phenotype (SASP). This phenomenon contributes to both aging and the development of cancer. The SASP comprises a variety of factors that regulate numerous functions, including the induction of secondary senescence, modulation of immune system activity, remodeling of the extracellular matrix, alteration of tissue structure, and promotion of cancer progression. Identifying key factors within the SASP is crucial for understanding the underlying mechanisms of senescence and developing effective strategies to counteract cellular senescence. Our research has specifically focused on investigating the role of IGFBP5, a component of the SASP observed in various experimental models and conditions. Through our studies, we have demonstrated that IGFBP5 actively contributes to promoting senescence and can induce senescence in neighboring cells. We have gained valuable insights into the mechanisms through which IGFBP5 exerts its pro-senescence effects. These mechanisms include its release following genotoxic stress, involvement in signaling pathways mediated by reactive oxygen species and prostaglandins, internalization via specialized structures called caveolae, and interaction with a specific protein known as RARα. By uncovering these mechanisms, we have advanced our understanding of the intricate role of IGFBP5 in the senescence process. The significance of IGFBP5 as a pro-aging factor stems from an in vivo study we conducted on patients undergoing Computer Tomography analysis. In these patients, we observed an elevation in circulating IGFBP5 levels in response to radiation-induced organismal stress. Globally, our findings highlight the potential of IGFBP5 as a promising therapeutic target for age-related diseases and cancer.

Simple Summary: The corneal epithelium is a protective barrier and refractive structure in the eye maintained through a complex regenerative process involving the lacrimal gland, tear film, and corneal nerves. This review explores the insulin-like growth factor (IGF) system and its role in corneal epithelium homeostasis. Emphasis is placed on the significance of limbal epithelial stem cells and potential therapeutic applications targeting the system components. The corneal epithelium, comprising three layers of cells, represents the outermost portion of the eye and functions as a vital protective barrier while concurrently serving as a critical refractive structure. Maintaining its homeostasis involves a complex regenerative process facilitated by the functions of the lacrimal gland, tear film, and corneal nerves. Crucially, limbal epithelial stem cells located in the limbus (transitional zone between the cornea and the conjunctiva) are instrumental for the corneal epithelium integrity by replenishing and renewing cells. Re-epithelialization failure results in persistent defects, often associated with various ocular conditions including diabetic keratopathy. The insulin-like growth factor (IGF) system is a sophisticated network of insulin and other proteins essential for numerous physiological processes. This review examines its role in maintaining the corneal epithelium homeostasis, with a special focus on the interplay with corneal limbal stem cells and the potential therapeutic applications of the system components. [ABSTRACT FROM AUTHOR]

Cells that are exposed to harmful genetic damage, either from internal or external sources, may undergo senescence if they are unable to repair their DNA. Senescence, characterized by a state of irreversible growth arrest, can spread to neighboring cells through a process known as the senescence-associated secretory phenotype (SASP). This phenomenon contributes to both aging and the development of cancer. The SASP comprises a variety of factors that regulate numerous functions, including the induction of secondary senescence, modulation of immune system activity, remodeling of the extracellular matrix, alteration of tissue structure, and promotion of cancer progression. Identifying key factors within the SASP is crucial for understanding the underlying mechanisms of senescence and developing effective strategies to counteract cellular senescence. Our research has specifically focused on investigating the role of IGFBP5, a component of the SASP observed in various experimental models and conditions. Through our studies, we have demonstrated that IGFBP5 actively contributes to promoting senescence and can induce senescence in neighboring cells. We have gained valuable insights into the mechanisms through which IGFBP5 exerts its pro-senescence effects. These mechanisms include its release following genotoxic stress, involvement in signaling pathways mediated by reactive oxygen species and prostaglandins, internalization via specialized structures called caveolae, and interaction with a specific protein known as RARα. By uncovering these mechanisms, we have advanced our understanding of the intricate role of IGFBP5 in the senescence process. The significance of IGFBP5 as a pro-aging factor stems from an in vivo study we conducted on patients undergoing Computer Tomography analysis. In these patients, we observed an elevation in circulating IGFBP5 levels in response to radiation-induced organismal stress. Globally, our findings highlight the potential of IGFBP5 as a promising therapeutic target for age-related diseases and cancer. [ABSTRACT FROM AUTHOR]

Insulin-like growth factor 1 (IGF-1) regulates dairy cow reproduction, while the paracrine IGF system locally influences fertility. In both systems, IGF-1 bioactivity is regulated through binding proteins (IGFBPs) inhibiting IGF-1 binding to its receptor (IGF1R). This study aimed to investigate a possible transfer between this endocrine and paracrine system. Therefore, blood and follicular fluid (FF) from postpartum dairy cows were analysed for ß-hydroxybutyrate (BHB), IGF-1, IGFBP-2, -3, -4, -5, and an IGFBP fragment in two study parts. The mRNA expression of IGFBP-2, IGFBP-4, IGF1R, and the pregnancy-associated plasma protein A (PAPP-A) in granulosa cells was measured. The results showed correlations between plasma and FF for IGF-1 (r = 0.57, p < 0.001) and IGFBP-2 (r = −0.57, p < 0.05). Blood BHB negatively correlated with IGF-1 in blood and FF and IGFBP-3, -5 and total IGFBP in blood (IGF-1 plasma: r = −0.26, p < 0.05; FF: r = −0.35, p < 0.05; IGFBP-3: r = −0.64, p = 0.006; IGFBP-5: r = −0.49, p < 0.05; total IGFBP: r = −0.52, p < 0.05). A negative correlation was found between IGFBP-2 expression and IGF-1 concentration in FF (r = −0.97, p = 0.001), while an IGFBP fragment positively correlated with IGF1R-mRNA in FF (r = 0.82, p = 0.042). These findings suggest a transfer and local regulation between the somatotropic axis and the follicular IGF system, linking the metabolic status with local effects on dairy cow fertility.

Abstract Background Insulin-like growth factor binding proteins (IGFBPs) are critical regulators of the biological activities of insulin-like growth factors. The IGFBP family plays diverse roles in different types of cancer, which we still lack comprehensive and pleiotropic understandings so far. Methods Multi-source and multi-dimensional data, extracted from The Cancer Genome Atlas (TCGA), Oncomine, Cancer Cell Line Encyclopedia (CCLE), and the Human Protein Atlas (HPA) was used for bioinformatics analysis by R language. Immunohistochemistry and qRT-PCR were performed to validate the results of the database analysis results. Bibliometrics and literature review were used for summarizing the research progress of IGFBPs in the field of tumor. Results The members of IGFBP gene family are differentially expressed in various cancer types. IGFBPs expression can affect prognosis of different cancers. The expression of IGFBPs expression is associated with multiple signal transduction pathways. The expression of IGFBPs is significantly correlated with tumor mutational burden, microsatellite instability, tumor stemness and tumor immune microenvironment. The qRT-PCR experiments verified the lower expression of IGFBP2 and IGFBP6 in gastric cancer and the lower expression of IGFBP6 in colorectal cancer. Immunohistochemistry validated a marked downregulation of IGFBP2 protein in gastric cancer tissues. The keywords co-occurrence analysis of IGFBP related publications in cancer showed relative research have been more concentrating on the potential of IGFBPs as tumor diagnostic and prognostic markers and developing cancer therapies. Conclusions These findings provide frontier trend of IGFBPs related research and new clues for identifying novel therapeutic targets for various cancers.

The corneal epithelium, comprising three layers of cells, represents the outermost portion of the eye and functions as a vital protective barrier while concurrently serving as a critical refractive structure. Maintaining its homeostasis involves a complex regenerative process facilitated by the functions of the lacrimal gland, tear film, and corneal nerves. Crucially, limbal epithelial stem cells located in the limbus (transitional zone between the cornea and the conjunctiva) are instrumental for the corneal epithelium integrity by replenishing and renewing cells. Re-epithelialization failure results in persistent defects, often associated with various ocular conditions including diabetic keratopathy. The insulin-like growth factor (IGF) system is a sophisticated network of insulin and other proteins essential for numerous physiological processes. This review examines its role in maintaining the corneal epithelium homeostasis, with a special focus on the interplay with corneal limbal stem cells and the potential therapeutic applications of the system components.

The pappalysin metalloproteinases, PAPP-A and PAPP-A2, have emerged as highly specific proteolytic enzymes involved in the regulation of insulin-like growth factor (IGF) signaling. The only known pappalysin substrates are a subset of the IGF binding proteins (IGFBPs), which bind IGF-I or IGF-II with high affinity to antagonize receptor binding. Thus, by cleaving IGFBPs, the pappalysins have the potential to increase IGF bioactivity and hence promote IGF signaling. This is relevant both in systemic and local IGF regulation, in normal and several pathophysiological conditions. Stanniocalcin-1 and -2 were recently found to be potent pappalysin inhibitors, thus comprising the missing components of a complete proteolytic system, the stanniocalcin-PAPP-A-IGFBP-IGF axis. Here, we provide the biological context necessary for understanding the properties of this molecular network, and we review biochemical data, animal experiments, clinical data, and genetic data supporting the physiological operation of this branch as an important part of the IGF system. However, although in vivo data clearly illustrate its power, it is a challenge to understand its subtle operation, for example, multiple equilibria and inhibitory kinetics may determine how, where, and when the IGF receptor is stimulated. In addition, literally all of the regulatory proteins have suspected or known activities that are not directly related to IGF signaling. How such activities may integrate with IGF signaling is also important to address in the future. [ABSTRACT FROM AUTHOR]

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While fetal growth is dependent on many factors, optimal placental function is a prerequisite for a normal pregnancy outcome. The majority of fetal growth-restricted (FGR) pregnancies result from placental insufficiency (PI). The insulin-like growth factors (IGF1 and IGF2) stimulate fetal growth and placental development and function. Previously, we demonstrated that in vivo RNA interference (RNAi) of the placental hormone, chorionic somatomammotropin (CSH), resulted in two phenotypes. One phenotype exhibits significant placental and fetal growth restriction (PI-FGR), impaired placental nutrient transport, and significant reductions in umbilical insulin and IGF1. The other phenotype does not exhibit statistically significant changes in placental or fetal growth (non-FGR). It was our objective to further characterize these two phenotypes by determining the impact of CSH RNAi on the placental (maternal caruncle and fetal cotyledon) expression of the IGF axis. The trophectoderm of hatched blastocysts (9 days of gestation, dGA) were infected with a lentivirus expressing either a non-targeting sequence (NTS RNAi) control or CSH-specific shRNA (CSH RNAi) prior to embryo transfer into synchronized recipient ewes. At ≈125 dGA, pregnancies were fitted with vascular catheters to undergo steady-state metabolic studies. Nutrient uptakes were determined, and tissues were harvested at necropsy. In both CSH RNAi non-FGR and PI-FGR pregnancies, uterine blood flow was significantly reduced (p ≤ 0.05), while umbilical blood flow (p ≤ 0.01), both uterine and umbilical glucose and oxygen uptakes (p ≤ 0.05), and umbilical concentrations of insulin and IGF1 (p ≤ 0.05) were reduced in CSH RNAi PI-FGR pregnancies. Fetal cotyledon IGF1 mRNA concentration was reduced (p ≤ 0.05) in CSH RNAi PI-FGR pregnancies, whereas neither IGF1 nor IGF2 mRNA concentrations were impacted in the maternal caruncles, and either placental tissue in the non-FGR pregnancies. Fetal cotyledon IGF1R and IGF2R mRNA concentrations were not impacted for either phenotype, yet IGF2R was increased (p ≤ 0.01) in the maternal caruncles of CSH RNAi PI-FGR pregnancies. For the IGF binding proteins (IGFBP1, IGFBP2, IGFBP3), only IGFBP2 mRNA concentrations were impacted, with elevated IGFBP2 mRNA in both the fetal cotyledon (p ≤ 0.01) and maternal caruncle (p = 0.08) of CSH RNAi non-FGR pregnancies. These data support the importance of IGF1 in placental growth and function but may also implicate IGFBP2 in salvaging placental growth in non-FGR pregnancies. [ABSTRACT FROM AUTHOR]

Persistent hyperglycemia resulting from diabetes mellitus causes microvascular lesions and long-term diabetic complications, such as nephropathy.The aim of the study was to analyze the levels of insulin-like growth factors (IGFs), their carrier proteins (IGFBP), and markers of kidney tissue damage (IL-18, L-FABP, cystatin C, NGAL, and KIM-1) in male rats with diabetes mellitus, tumor growth, and their combination.Materials and methods. The study included white outbred male rats (n = 32) weighing 180–220 g. The animals were divided into four groups (n = 8 each): group 1 – intact animals; controls (2) – animals with diabetes mellitus; controls (3) – animals with Guerin carcinoma; experimental group (4) – animals with Guerin carcinoma against the background of diabetes mellitus. Levels of IGF-1, IGF-2, IGFBP-1, IGFBP-2 and markers of acute kidney injury (IL-18, L-FABP, cystatin С, NGAL, and KIM-1) were determined in the kidney homogenates using enzyme-linked immunosorbent assay.Results. Increased levels of acute kidney injury markers were found in the kidneys of male rats with diabetes mellitus alone and in combination with Guerin carcinoma. In the animals with diabetes mellitus, the levels of IGF-1, IGFBP-1, and IGFBP-2 were decreased on average by 1.3 times, and the level of IGF-2 was increased by 2.1 times compared with the values in the intact male rats. The elevation of IGF-2 / IGF-1 on average by 2.8 times indicated increasing hypoglycemia in the kidney tissue of the animals with diabetes mellitus and in the experimental group with diabetes mellitus and Guerin carcinoma. In the kidney tissues of the rats with Guerin carcinoma, IGF-1 and IGF-2 were elevated on average by 1.5 times, and IGFBP-2 was decreased by 1.7 times. In the animals with malignant tumors growing against the background of diabetes mellitus, IGF-2 and IGFBP-1 were increased by 2.3 and 1.7 times, respectively, and the levels of IGF-1 and IGFBP-2 were similar to those in the intact animals.Conclusion. The study demonstrated abnormalities in the metabolic profile of the kidneys in male rats with experimental diabetes mellitus, Guerin carcinoma, and their combination.

Background: Insulin-like growth factor binding proteins (IGFBPs) are critical regulators of the biological activities of insulin-like growth factors. The IGFBP family plays diverse roles in different types of cancer, which we still lack comprehensive and pleiotropic understandings so far. Methods: Multi-source and multi-dimensional data, extracted from The Cancer Genome Atlas (TCGA), Oncomine, Cancer Cell Line Encyclopedia (CCLE), and the Human Protein Atlas (HPA) was used for bioinformatics analysis by R language. Immunohistochemistry and qRT-PCR were performed to validate the results of the database analysis results. Bibliometrics and literature review were used for summarizing the research progress of IGFBPs in the field of tumor. Results: The members of IGFBP gene family are differentially expressed in various cancer types. IGFBPs expression can affect prognosis of different cancers. The expression of IGFBPs expression is associated with multiple signal transduction pathways. The expression of IGFBPs is significantly correlated with tumor mutational burden, microsatellite instability, tumor stemness and tumor immune microenvironment. The qRT-PCR experiments verified the lower expression of IGFBP2 and IGFBP6 in gastric cancer and the lower expression of IGFBP6 in colorectal cancer. Immunohistochemistry validated a marked downregulation of IGFBP2 protein in gastric cancer tissues. The keywords co-occurrence analysis of IGFBP related publications in cancer showed relative research have been more concentrating on the potential of IGFBPs as tumor diagnostic and prognostic markers and developing cancer therapies. Conclusions: These findings provide frontier trend of IGFBPs related research and new clues for identifying novel therapeutic targets for various cancers. [ABSTRACT FROM AUTHOR]

Acute low-salinity induces multiple stress responses and significantly impact the health of aquatic animals. However, the molecular regulation network and metabolic adaptation of low salinity stress in aquatic organisms remain unclear. The insulin-like growth factor binding proteins (IGFBPs) and insulin/IGF-like signaling (IIS)-target of rapamycin (TOR) signaling cascade are evolutionarily conserved regulators known to play crucial roles in response to various stressors. In this study, we used the euryhaline Pacific white shrimp (Litopenaeus vannamei) as a model organism to investigate the involvement of IGFBP and IIS-TOR signaling cascade in acute low-salinity response. We found seven LvIGFBPs and evaluated 18s as one of most stable internal reference genes under acute low salinity stress. The expression of LvIGFBP4, LvSIBD1, and LvSIBD2 was significantly increased after 6-hours 5‰ salinity treatment. LvSIBD2 was specifically expressed on the surface of gill branch axis. Acute low-salinity significantly induced the phosphorylation of Akt and S6K in the gill but not in the muscle. We found acute low-salinity increased the levels of total essential amino acids, including leucine and arginine, while decreasing the total non-essential amino acid levels in the gill. Furthermore, glucose and key metabolites in glycolysis and tricarboxylic acid cycle (TCA cycle) were increased, indicating remodeling of energy metabolism occurred. These results demonstrate the involvement of IGFBP and IIS-TOR signaling cascade in acute low-salinity response and provide new insights into understanding the mechanism of osmoregulation in euryhaline crustacean species.

Aim. To investigate the content of insulin-like growth factor (IGF)-1, IGF-2, and their transporter proteins IGFBP-1 and IGFBP in the liver of rats with experimental diabetes, Guerin’s carcinoma, and their combination.Materials and methods. The experiment was carried out on 64 white outbred rats of both sexes, which were divided into 4 groups of 8 animals each: group 1 – intact animals, group 2 – animals with experimental diabetes, group 3 – animals with subcutaneously inoculated Guerin’s carcinoma, group 4 – animals with experimental diabetes and subcutaneously inoculated Guerin’s carcinoma. In the study, biochemical and statistical analyses and enzyme immunoassays were performed.Results. In the liver of the outbred rats, sex specificity in the content of insulin-like growth factors and IGFBP-1 was established: the levels of IGF-1, IGF-2, and IGFBP-1 in males were lower than in females. It was shown that the development of diabetes mellitus and the growth of Guerin’s carcinoma led to changes in the sex-specific components in the rat liver.Conclusion. The growth of Guerin’s carcinoma and the progression of diabetes mellitus cause multidirectional changes in IGF and IGFBP levels in the liver of females and unidirectional changes in the liver of males. Following the growth of Guerin’s carcinoma against the background of diabetes mellitus, sex-specific differences in the content of the studied parameters were minimized. It was shown that diabetes mellitus changed the metabolic profile of the liver in the animals of both sexes.

Abstract Background Enhancer of zeste homolog 2 (EZH2)-mediated histone 3 lysine 27 trimethylation (H3K27me3) is a transcription silencing mark, which is indispensable for cell lineage specification at the early blastocyst stage. This epigenetic repression is maintained in placental cytotrophoblasts but is lifted when cytotrophoblasts differentiate into syncytiotrophoblasts. However, the physiological impact of this lift remains elusive. Here, we investigated whether lifting EZH2-mediated H3K27me3 during syncytialization upregulates the expression of a short secretory isoform of a disintegrin and metalloprotease 12 (ADAM12-S), a well-recognized placenta-derived protease that cleaves insulin-like growth factor binding protein 3 to increase insulin-like growth factor (IGF) bioavailability for the stimulation of fetoplacental growth. The transcription factor and the upstream signal involved were also explored. Methods Human placenta tissue and cultured primary human placental cytotrophoblasts were utilized to investigate the role of EZH2-mediated H3K27me3 in ADAM12-S expression and the associated transcription factor and upstream signal during syncytialization. A mouse model was used to examine whether inhibition of EZH2-mediated H3K27me3 regulates placental ADAM12-S expression and fetoplacental growth. Results EZH2 and ADAM12 are distributed primarily in villous cytotrophoblasts and syncytiotrophoblasts, respectively. Increased ADAM12-S expression, decreased EZH2 expression, and decreased EZH2/H3K27me3 enrichment at the ADAM12 promoter were observed during syncytialization. Knock-down of EZH2 further increased ADAM12-S expression in trophoblasts. Syncytialization was also accompanied by increased STAT5B expression and phosphorylation as well as its enrichment at the ADAM12 promoter. Knock-down of STAT5B attenuated ADAM12-S expression during syncytialization. Epidermal growth factor (EGF) was capable of inducing ADAM12-S expression via stimulation of STAT5B expression and phosphorylation during syncytialization. Mouse studies revealed that administration of an EZH2 inhibitor significantly increased ADAM12-S levels in maternal blood and fetoplacental weights along with decreased H3K27me3 abundance and increased ADAM12-S expression in the placenta. Conclusions Lifting EZH2-mediated H3K27me3 increases ADAM12-S expression during syncytialization with the participation of EGF-activated STAT5B, which may lead to elevation of ADAM12-S level in maternal blood resulting in increased IGF bioavailability for the stimulation of fetoplacental growth in pregnancy. Our studies suggest that the role of EZH2-mediated H3K27me3 may switch from cell lineage specification at the early blastocyst stage to regulation of fetoplacental growth in later gestation.

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. [ABSTRACT FROM AUTHOR]

Introduction/Aims: Spinal muscular atrophy (SMA) is an inherited neuromuscular disease caused by survival motor neuron (SMN) protein deficiency. Insulin‐like growth factor‐I (IGF‐I) is a myotrophic and neurotrophic factor that has been reported to be dysregulated in in vivo SMA model systems. However, detailed analyses of the IGF‐I system in SMA patients are missing. In this study, we analyzed the components of the IGF‐I system in serum and archived skeletal muscle biopsies of SMA patients. Methods: Serum IGF‐I, IGF binding protein (IGFBP)‐3, and IGFBP‐5 levels were analyzed in 11 SMA patients and 13 healthy children by immunoradiometric and enzyme‐linked immunosorbent assays. The expression of IGF‐I, IGF‐I receptor, and IGFBP‐5 proteins was investigated by immunofluorescence analysis in the archived skeletal muscle biopsies of nine SMA patients, six patients with non‐SMA‐related neuromuscular disease and atrophic fibers in muscle biopsy, and four controls. Results: A significant decrease in IGF‐I levels (mean ± SD: −1.39 ± 1.46 vs. 0.017 ± 0.83, p =.02) and increase in IGFBP‐5 levels (mean ± SD: 2358.5 ± 1617.4 ng/mL vs. 1003.4 ± 274.3 ng/mL, p =.03) were detected in serum samples of SMA patients compared to healthy controls. Increased expression of IGF‐I, IGF‐I receptor, and IGFBP‐5 was detected in skeletal muscle biopsies of SMA patients and non‐SMA neuromuscular diseases, indicating atrophy‐specific alterations in the pathway. Discussion: Our findings suggested that the components of the IGF‐I system are altered in SMA patients at both the systemic and tissue‐specific levels. [ABSTRACT FROM AUTHOR]

Protein delivery is often used in tissue engineering applications to control differentiation processes, but is limited by protein instability and cost. An alternative approach is to control the cellular microenvironment through biomaterial-mediated sequestration of cell-secreted proteins important to differentiation. Thus, we utilized heparin-based microparticles to modulate cellular differentiation via protein sequestration in an in vitro model system of endochondral ossification. Heparin and poly(ethylene-glycol) (PEG; a low-binding material control)-based microparticles were incorporated into ATDC5 cell spheroids or incubated with ATDC5 cells in transwell culture. Reduced differentiation was observed in the heparin microparticle group as compared to PEG and no microparticle-containing groups. To determine if observed changes were due to sequestration of cell-secreted protein, the proteins sequestered by heparin microparticles were analyzed using SDS-PAGE and mass spectrometry. It was found that heparin microparticles bound insulin-like growth factor binding proteins (IGFBP)-3 and 5. When incubated with a small-molecule inhibitor of IGFBPs, NBI 31772, a similar delay in differentiation of ATDC5 cells was observed. These results indicate that heparin microparticles modulated chondrocytic differentiation in this system via sequestration of cell-secreted protein, a technique that could be beneficial in the future as a means to control cellular differentiation processes. STATEMENT OF SIGNIFICANCE:In this work, we present a proof-of-principle set of experiments in which heparin-based microparticles are shown to modulate cellular differentiation through binding of cell-secreted protein. Unlike existing systems that rely on expensive protein with limited half-lives to elicit changes in cellular behavior, this technique focuses on temporal modulation of cell-generated proteins. This technique also provides a biomaterials-based method that can be used to further identify sequestered proteins of interest. Thus, this work indicates that glycosaminoglycan-based biomaterial approaches could be used as substitutes or additions to traditional methods for modulating and identifying the cell-secreted proteins involved in directing cellular behavior.

Purpose of the study. Diabetes mellitus (DM) is considered an independent risk factor for higher cancer incidence and death rates. The system of insulin-like growth factors and their carrier proteins (IGF and IGFBP) and hyperglycemia create favorable conditions for the proliferation and metastasis of cancer cells.Materials and methods. Outbred male and female rats were divided into groups (n = 8 each): controls - with Guerin's carcinoma; main group - Guerin's carcinoma growing in presence of DM. Experimental DM was reproduces in animals by the single intraperitoneal alloxan injection (150 mg/kg body weight). After 10 days of the carcinoma growth, levels of IGF and IGFBP in the tumor and in it's perifocal area were measured using ELISA.Results. DM in females upregulated levels of glucose both in the tumor and in perifocal tissues by 1.8 (p < 0.05) and 8.1 times, respectively, but caused opposite changes in IGF-I - it's increase by 6.3 times in the tumor and decrease by 3.2 times in the perifocal area; as a result, such tumors with small primary nodes were more "aggressive" and actively metastasized. In males, induced DM downregulated levels of glucose, IGF-II and IGFBP2 in the carcinoma by 8.4, 3.1 and 1.7 (p < 0.05) times, respectively, and increased levels of IGF-I and IGFBP2 by 1.4 and 1.3 times (p < 0.05) in the perifocal area without changing glucose levels; as a result, tumor volumes exceeded the values in the standard growth, without metastasizing into visceral organs.Conclusion. We revealed gender differences in changing levels of glucose and IGF both in the tumor and in it's perifocal tissue in rats with Guerin's carcinoma growing in presence of DM; these differences could determine different tumor growth dynamics in male and female rats.

Context: Pappalysins (PAPP-A, PAPP-A2) modulate body growth by increasing insulin-like growth factor I (IGF-I) bioavailability through cleavage of insulin-like growth factor binding proteins (IGFBPs) and are inhibited by stanniocalcins (STC1, STC2). Normative data on these novel factors, as well as on free IGF-I and uncleaved fractions of IGFBPs, are not well established. Objective: This work aimed to determine serum concentrations of PAPP-A, PAPP-A2, STC1, and STC2 in relationship with other growth hormone (GH)-IGF axis parameters during development. Methods: Full-term newborns (150; gestational age: 39.30 ± 1.10 weeks), 40 preterm newborns (30.87 ± 3.35 weeks), and 1071 healthy individuals (aged 1-30 years) were included in the study and divided according to their Tanner stages (males and females): I:163 males, 154 females; II:100 males, 75 females; III:83 males, 96 females; IV: 77 males, 86 females; and V:109 males, 128 females. Results: Serum concentrations of PAPP-A, PAPP-A2, STC1, STC2, IGFBP-2, total IGFBP-4, and total IGFBP-5 were elevated at birth and declined throughout childhood. In postnatal life, PAPP-A2 concentrations decreased progressively in concomitance with the free/total IGF-I ratio; however, stanniocalcin concentrations remained stable. PAPP-A2 concentrations positively correlated with the free/total IGF-I ratio (r = +0.28; P < .001) and negatively with the intact/total IGFBP-3 ratio (r = -0.23; P < .001). PAPP-A concentrations inversely correlated with intact/total IGFBP-4 ratio (r = -0.21; P < .001), with PAPP-A concentrations being lower in females at all ages. Association studies indicate the importance of stanniocalcins and pappalysins in the control of this axis in an age-specific manner. Conclusion: This study provides reference values of pappalysins and stanniocalcins, which modulate IGF-I activity by changing the concentrations of cleaved and uncleaved IGFBPs. [ABSTRACT FROM AUTHOR]

Background: Enhancer of zeste homolog 2 (EZH2)-mediated histone 3 lysine 27 trimethylation (H3K27me3) is a transcription silencing mark, which is indispensable for cell lineage specification at the early blastocyst stage. This epigenetic repression is maintained in placental cytotrophoblasts but is lifted when cytotrophoblasts differentiate into syncytiotrophoblasts. However, the physiological impact of this lift remains elusive. Here, we investigated whether lifting EZH2-mediated H3K27me3 during syncytialization upregulates the expression of a short secretory isoform of a disintegrin and metalloprotease 12 (ADAM12-S), a well-recognized placenta-derived protease that cleaves insulin-like growth factor binding protein 3 to increase insulin-like growth factor (IGF) bioavailability for the stimulation of fetoplacental growth. The transcription factor and the upstream signal involved were also explored.Methods: Human placenta tissue and cultured primary human placental cytotrophoblasts were utilized to investigate the role of EZH2-mediated H3K27me3 in ADAM12-S expression and the associated transcription factor and upstream signal during syncytialization. A mouse model was used to examine whether inhibition of EZH2-mediated H3K27me3 regulates placental ADAM12-S expression and fetoplacental growth.Results: EZH2 and ADAM12 are distributed primarily in villous cytotrophoblasts and syncytiotrophoblasts, respectively. Increased ADAM12-S expression, decreased EZH2 expression, and decreased EZH2/H3K27me3 enrichment at the ADAM12 promoter were observed during syncytialization. Knock-down of EZH2 further increased ADAM12-S expression in trophoblasts. Syncytialization was also accompanied by increased STAT5B expression and phosphorylation as well as its enrichment at the ADAM12 promoter. Knock-down of STAT5B attenuated ADAM12-S expression during syncytialization. Epidermal growth factor (EGF) was capable of inducing ADAM12-S expression via stimulation of STAT5B expression and phosphorylation during syncytialization. Mouse studies revealed that administration of an EZH2 inhibitor significantly increased ADAM12-S levels in maternal blood and fetoplacental weights along with decreased H3K27me3 abundance and increased ADAM12-S expression in the placenta.Conclusions: Lifting EZH2-mediated H3K27me3 increases ADAM12-S expression during syncytialization with the participation of EGF-activated STAT5B, which may lead to elevation of ADAM12-S level in maternal blood resulting in increased IGF bioavailability for the stimulation of fetoplacental growth in pregnancy. Our studies suggest that the role of EZH2-mediated H3K27me3 may switch from cell lineage specification at the early blastocyst stage to regulation of fetoplacental growth in later gestation. [ABSTRACT FROM AUTHOR]

Introduction and Aims: Insulin-like growth factor 1 is modulated by the insulin-like growth factor-binding proteins (IGFBPs) that are synthesized in the liver. The aim of the present study was to evaluate the concentrations of IGFBPs 1–7 in patients with chronic hepatitis C and study their association with fibrosis stage. Patients and methods: A prospective, cross-sectional study was conducted that included patients with chronic hepatitis C. The stages of fibrosis were determined through FibroTest and FibroScan and the patients were compared with a control group. Serum levels of IGFBPs 1–7 were quantified through multiple suspension arrays. The Kruskal-Wallis test, Mann-Whitney U test, Spearman’s correlation, and ROC curves were used for the statistical analysis. Results: Upon comparing the patients and controls, the highest concentrations were found in IGFBPs 1, 2, 4, and 7 (p = 0.02, 0.002, 0.008, and

Plant polyphenols, including polyphenol-rich extracts, display various biological activities. They have been found to act as, among others, anti-oxidative, anti-proliferative, pro-apoptotic, anti-angiogenic and anti-inflammatory agents. These compounds can modulate the activities of some functional proteins and receptors, such as insulin-like growth factor system, including IGF, IGF-1R, and IGFBPs proteins. The IGF system plays an important role in cell processes such as proliferation, differentiation and apoptosis, as well as in carcinogenesis. Plant polyphenols also have the ability to prevent the development of cancer, modulating some of the signal transduction pathways (PI3K/Akt and MAPK/ERK) associated with the process. Their variety of mechanisms of action offers hope that both individual phenolic compounds and extracts may be used for the prevention or inhibition of carcinogenesis. This review discusses the impact of natural polyphenols and polyphenol-rich extracts on the expression and activity of IGF-1, IGF-R, and IGFBP in various cancers.

Beside the pulmonary vasoconstriction observed in pulmonary arterial hypertension (PAH), severe proliferative and antiapoptotic cellular phenotypes result in vascular remodelling. Many recent findings indicate similarities between PAH and tumour pathology. For instance, insulin-like growth factor (IGF)-1 signalling, which is known to promote tumour development, is implicated in PAH. Higher circulating IGF binding protein (IGFBP)-1 levels are associated with worse survival in PAH. The present study aimed to investigate the relationship between plasma levels of various tumour-related biomarkers and PAH. Methods: IGFBP-1, -2 and -7, along with other tumour-related biomarkers, were measured in plasma from 48 treatment-naïve PAH patients and 16 healthy controls, using proximity extension assays. Among the PAH patients, 33 were also studied at an early treatment follow-up. Results: Plasma IGFBP-1 (p <.003), IGFBP-2 (p <.001), IGFBP-7 (p <.008), vimentin (p <.001), carbonic anhydrase 9 (p <.001), S100A11 (p <.001), human epididymis protein 4 (p <.001) and folate receptor-α (p <.004) were elevated in PAH, compared to controls. IGFBP-1 exhibited the most interesting correlations to clinical parameters and was selected for further analyses. IGFBP-1 correlated specifically to N-terminal prohormone of brain natriuretic peptide (NT-proBNP) (r = 0.44, p <.002), mean right atrial pressure (r = 0.41, p <.004), venous oxygen saturation (r = –0.43, p <.003), cardiac index (r = –0.32, p <.03) and 6-minute walking distance (r = –0.29, p <.05). Plasma IGFBP-1 also correlated to risk scores based on the European Society of Cardiology/European Respiratory Society (ESC/ERS) PAH guidelines (r = 0.43, p <.003) and the REVEAL model (r = 0.46, p <.001). PAH patients with supra-median baseline IGFBP-1 levels showed a trend for worse overall survival than those with infra-median levels (p =.087). IGFBP-1 was unaltered between baseline and an early treatment follow-up. However, IGFBP-1 changes, between baseline and follow-up, correlated to changes in NT-proBNP (r = 0.48, p <.006). Conclusion: Plasma IGFBP-1 levels at PAH diagnosis show moderate association to NT-proBNP and hemodynamics as well as with ESC/ERS and REVEAL risk scores. [ABSTRACT FROM AUTHOR]

Much information is currently available for molecules in early odontogenesis, but there is limited knowledge regarding terminal cytodifferentiation of ameloblasts and odontoblasts for the determination of normal crown morphology. The present differential display PCR (DD-PCR) revealed that insulin-like growth factor-binding protein 5 (IGFBP5) was differentially expressed in molar tooth germs between the cap (before crown mineralization) and root formation (after crown mineralization) stages. Real-time PCR confirmed that the expression levels of IGFBP1–4 were not significantly changed but those of IGFBP5–7 were upregulated in a time-dependent manner. Immunoreactivities for IGFBP5–7 were hardly seen in molar germs at the cap/early bell stage and protective-stage ameloblasts at the root formation stage. However, the reactivity was strong in odontoblasts and maturation-stage ameloblasts, which are morphologically and functionally characterized by wide intercellular space and active enamel matrix mineralization. The localization of each IGFBP was temporospatial. IGFBP5 was localized in the nuclei of fully differentiated odontoblasts and ameloblasts, while IGFBP6 was localized in the apical cytoplasm of ameloblasts and odontoblasts with dentinal tubules, and IGFBP7 was mainly found in the whole cytoplasm of odontoblasts and the intercellular space of ameloblasts. IGFBP silencing using specific siRNAs upregulated representative genes for dentinogenesis and amelogenesis, such as DMP1 and amelogenin, respectively, and augmented the differentiation media-induced mineralization, which was confirmed by alizarin red s and alkaline phosphatase staining. These results suggest that IGFBP5–7 may play independent and redundant regulatory roles in late-stage odontogenesis by modulating the functional differentiation of ameloblasts and odontoblasts. [ABSTRACT FROM AUTHOR]

Background: Prepubertal children with obesity frequently have enhanced growth, accelerated skeletal maturation and changes in the GH-IGF axis. However, the involvement of pappalysins (PAPP-A, PAPP-A2) and stanniocalcins (STC1, STC2) as regulators of IGF bioavailability has not been studied in obesity., Objective: We aimed to determine the effects of childhood obesity and weight reduction on serum levels of PAPP-A, PAPP-A2, STC1 and STC2 and their relationship with IGF bioavailability, growth, and other components of the GH-IGF system., Patients and Methods: Prepubertal children with severe obesity (150, 50% males/females, age: 7.72 ± 2.05 years, BMI z-score: 4.95 ± 1.70, height z-score: 1.28 ± 1.04) were studied at diagnosis and after a minimum of 0.5 BMI z-score reduction. Two hundred and six healthy age- and sex-matched children were used as controls., Results: Children with obesity had decreased serum concentrations of PAPP-A, PAPP-A2 and STC2, but increased total and free IGF-I (fIGF-I), intact IGFBP-3, ALS, IGF-II and insulin levels, with no difference in the free/total IGF-I ratio. Neither the standardized BMI nor height correlated with any biochemical parameter analyzed. A decrease in IGF-II, insulin, and ALS with an increase in IGFBP-2 and -5, STC2 and PAPP-A were observed after weight loss., Conclusion: Increased circulating total and free IGF-I, insulin and IGF-II may all contribute to the increased rate of prepubertal growth and bone maturation observed in children with obesity, with STC2 possibly being involved., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Abstract Background Pericytes and endothelial cells are critical cellular components of the blood-brain barrier (BBB) and play an important role in neuroinflammation. To date, the majority of inflammation-related studies in endothelia and pericytes have been carried out using immortalised cell lines or non-human-derived cells. Whether these are representative of primary human cells is unclear and systematic comparisons of the inflammatory responses of primary human brain-derived pericytes and endothelia has yet to be performed. Methods To study the effects of neuroinflammation at the BBB, primary brain endothelial cells and pericytes were isolated from human biopsy tissue. Culture purity was examined using qPCR and immunocytochemistry. Electrical cell-substrate impedance sensing (ECIS) was used to determine the barrier properties of endothelial and pericyte cultures. Using immunocytochemistry, cytometric bead array, and ECIS, we compared the responses of endothelia and pericytes to a panel of inflammatory stimuli (IL-1β, TNFα, LPS, IFN-γ, TGF-β1, IL-6, and IL-4). Secretome analysis was performed to identify unique secretions of endothelia and pericytes in response to IL-1β. Results Endothelial cells were pure, moderately proliferative, retained the expression of BBB-related junctional proteins and transporters, and generated robust TEER. Both endothelia and pericytes have the same pattern of transcription factor activation in response to inflammatory stimuli but respond differently at the secretion level. Secretome analysis confirmed that endothelia and pericytes have overlapping but distinct secretome profiles in response to IL-1β. We identified several cell-type specific responses, including G-CSF and GM-CSF (endothelial-specific), and IGFBP2 and IGFBP3 (pericyte-specific). Finally, we demonstrated that direct addition of IL-1β, TNFα, LPS, and IL-4 contributed to the loss of endothelial barrier integrity in vitro. Conclusions Here, we identify important cell-type differences in the inflammatory response of brain pericytes and endothelia and provide, for the first time, a comprehensive profile of the secretions of primary human brain endothelia and pericytes which has implications for understanding how inflammation affects the cerebrovasculature.

Insulin-like growth factors (IGF-1 and IGF-2) and insulin-like growth factor-binding proteins (IGFBP-1 to -7) are involved in the regulation of cell proliferation and differentiation and may be associated with various metabolic parameters. The aim of our study was to compare levels of IGFs and IGFBPs and the expressions of their genes in children before and after hematopoietic stem cell transplantation (HSCT) to assess their potential as markers of late metabolic complications of HSCT. We also conducted additional comparisons with healthy controls and of correlations of IGF and IGFBP levels with anthropometric and biochemical parameters. We analyzed 19 children treated with HSCT and 21 healthy controls. We found no significant differences in the levels of IGFs and IGFBPs and expressions of their genes before and after HSCT, while IGF and IGFBP levels were significantly lower in children treated with HSCT compared with controls. We conclude that our results did not reveal significant differences between the levels of IGFs and IGFBPs before and after HSCT, which would make them obvious candidates for markers of late complications of the procedure in children. However, due to the very low number of patients this conclusion must be taken with caution and may be altered by further research.

The insulin and insulin-like signaling (IIS) network regulates cellular processes including pre- and postnatal growth, cellular development, wound healing, reproduction, and longevity. Despite their importance in the physiology of vertebrates, the study of the specific functions of the top regulators of the IIS network, insulin-like growth factors (IGFs) and IGF binding proteins (IGFBPs), has been mostly limited to a few model organisms. To expand our understanding of this network, we performed quantitative gene expression of IGF hormones in liver and qualitative expression of IGFBPs across tissues and developmental stages in a model reptile, the brown anole lizard (Anolis sagrei). We found that lizards express IGF2 across all life stages (preoviposition embryos to adulthood) and at a higher level than IGF1, which is opposite to patterns seen in laboratory rodents but similar to those seen in humans and other vertebrate models. IGFBP expression was ubiquitous across tissues (brain, gonad, heart, liver, skeletal muscle, tail, and regenerating tail) in adults, apart from IGFBP5, which was variable. These findings provide an essential foundation for further developing the anole lizard as a physiological and biomedical reptile model, as well as expanding our understanding of the function of the IIS network across species. [ABSTRACT FROM AUTHOR]

The molecular processes of aging are very heterogenic and not fully understood. Studies on rare progeria syndromes, which display an accelerated progression of physiological aging, can help to get a better understanding. Pseudoxanthoma elasticum (PXE) caused by mutations in the ATP-binding cassette sub-family C member 6 (ABCC6) gene shares some molecular characteristics with such premature aging diseases. Thus, this is the first study trying to broaden the knowledge of aging processes in PXE patients. In this study, we investigated aging associated biomarkers in primary human dermal fibroblasts and sera from PXE patients compared to healthy controls. Determination of serum concentrations of the aging biomarkers eotaxin-1 (CCL11), growth differentiation factor 11 (GDF11) and insulin-like growth factor 1 (IGF1) showed no significant differences between PXE patients and healthy controls. Insulin-like growth factor binding protein 3 (IGFBP3) showed a significant increase in serum concentrations of PXE patients older than 45 years compared to the appropriate control group. Tissue specific gene expression of GDF11 and IGFBP3 were significantly decreased in fibroblasts from PXE patients compared to normal human dermal fibroblasts (NHDF). IGFBP3 protein concentration in supernatants of fibroblasts from PXE patients were decreased compared to NHDF but did not reach statistical significance due to potential gender specific variations. The minor changes in concentration of circulating aging biomarkers in sera of PXE patients and the significant aberrant tissue specific expression seen for selected factors in PXE fibroblasts, suggests a link between ABCC6 deficiency and accelerated aging processes in affected peripheral tissues of PXE patients. [ABSTRACT FROM AUTHOR]

• Rockfish experiencing feeding or fasting were treated with growth hormone (Gh) • Liver igf1 expression was upregulated by Gh in fed fish but unaffected by Gh in fasted fish. • Fasted rockfish had lower liver mRNA abundances for Gh receptors ghr1 and ghr2. • Fasting reduced liver levels of phosphorylated Jak2 and Stat5(A/B) proteins. • Fasting altered liver mRNAs encoding socs2 and - 3 genes and igfpbs1a , -1b , -2b, and -3a. Growth hormone (Gh) regulates growth in part by stimulating the liver to synthesize and release insulin-like growth factor-1 (Igf1), which then promotes somatic growth. However, for fish experiencing food limitation, elevated blood Gh can occur even with low circulating Igf1 and slow growth, suggesting that nutritional stress can alter the sensitivity of liver Igf1 synthesis pathways to Gh. Here, we examined how recent feeding experience affected Gh regulation of liver Igf1 synthesis pathways in juvenile gopher rockfish (Sebastes carnatus) to illuminate mechanisms underlying the nutritional modulation of Igf1 production. Juvenile gopher rockfish were maintained under conditions of feeding or complete food deprivation (fasting) for 14 d and then treated with recombinant sea bream (Sparus aurata) Gh or saline control. Gh upregulated hepatic igf1 mRNA levels in fed fish but not in fasted fish. The liver of fasted rockfish also showed a lower relative abundance of gene transcripts encoding teleost Gh receptors 1 (ghr1) and 2 (ghr2), as well as reduced protein levels of phosphorylated janus tyrosine kinase 2 (pJak2) and signal transducer and activator of transcription 5 (pStat5), which function to induce igf1 gene transcription following Gh binding to Gh receptors. Relative hepatic mRNA levels for suppressors of cytokine signaling (Socs) genes socs2 , socs3a , and socs3b were also lower in fasted rockfish. Socs2 can suppress Gh activation of Jak2/Stat5, and fasting-related variation in socs expression may reflect modulated inhibitory control of igf1 gene transcription. Fasted rockfish also had elevated liver mRNA abundances for lipolytic hormone-sensitive lipase 1 (hsl1) and Igf binding proteins igfbp1a, -1b and –3a , reduced liver mRNAs encoding igfbp2b and an Igfbp acid labile subunit-like (igfals) gene, and higher transcript abundances for Igf1 receptors igf1ra and igf1rb in skeletal muscle. Together, these findings suggest that food deprivation impacts liver Igf1 responsiveness to Gh via multiple mechanisms that include a downregulation of hepatic Gh receptors, modulation of the intracellular Jak2/Stat5 transduction pathway, and possible shifts in Socs-inhibitory control of igf1 gene transcription, while also demonstrating that these changes occur in concert with shifts in liver Igfbp expression and muscle Gh/Igf1 signaling pathway components. [ABSTRACT FROM AUTHOR]

Marine biology professors Chris Lowe and Kevin Kelley of California State University, Long Beach were funded to examine the physiological effects of catch-and-release practices on California sheephead. A major focus of the research was to gauge stress levels in fish by measuring hormonal changes—in particular levels of the stress hormone cortisol and insulin-like growth factor, which regulate growth, metabolism and tissue repair. They also tagged fish to study mortality rates of released fish and to monitor behavioral changes that might reduce an animal’s long-term chances of survival.

Insulin-like growth factors (IGFs) and insulin-like growth-factor-binding proteins (IGFBPs) regulate cell proliferation and differentiation and may be of importance in obesity development. The aim of the study was to analyze the expression of chosen IGF-axis genes and the concentration of their protein products in 28 obese children (OB) and 34 healthy control (HC), and their correlation with essential parameters associated with childhood obesity. The gene expression of IGFBP7 was higher, and the expression of IGF2 and IGFBP1 genes was lower in the OB. The expression of IGFBP6 tended to be lower in OB. IGFBP4 concentration was significantly higher, and IGFBP3 tended to be higher in the OB compared to the HC, while IGFBP1, IGFBP2, and IGFBP6 were significantly lower, and IGFBP7 tended to be lower in OB. We found numerous correlations between IGFs and IGFBP concentration and obesity metabolic parameters. IGFBP6 correlated positively with apelin, cholecystokinin, glucagone-like peptide-1, and leptin receptor. These peptides were also significantly lower in obese children in our study. The biological role of decreased levels of IGFBP6 in obese children needs further investigation.

The GH/IGF axis is a major regulator of bone formation and resorption and is essential to the achievement of normal skeleton growth and homeostasis. Beyond its key role in bone physiology, the GH/IGF axis has also major pleiotropic endocrine and autocrine/paracrine effects on mineralized tissues throughout life. This article aims to review the literature on GH, IGFs, IGF binding proteins, and their respective receptors in dental tissues, both epithelium (enamel) and mesenchyme (dentin, pulp, and tooth-supporting periodontium). The present review re-examines and refines the expression of the elements of the GH/IGF axis in oral tissues and their in vivo and in vitro mechanisms of action in different mineralizing cell types of the dento-alveolar complex including ameloblasts, odontoblasts, pulp cells, cementoblasts, periodontal ligament cells, and jaw osteoblasts focusing on cell-specific activities. Together, these data emphasize the determinant role of the GH/IGF axis in physiological and pathological development, morphometry, and aging of the teeth, the periodontium, and oral bones in humans, rodents, and other vertebrates. These advancements in oral biology have elicited an enormous interest among investigators to translate the fundamental discoveries on the GH/IGF axis into innovative strategies for targeted oral tissue therapies with local treatments, associated or not with materials, for orthodontics and the repair and regeneration of the dento-alveolar complex and oral bones.

Abstract Background The insulin growth factor (IGF) pathway has been proposed as a potential therapeutic target in bladder cancer. We characterized the expression of components of the IGF pathway — insulin growth factor receptors (INSR, IGF1R, IGF2R), ligands (INS, IGF1, IGF2), and binding proteins (IGFBP1–7, IGF2BP1–3) — in bladder cancer and its correlation with IGF1R activation, and the anti-proliferative efficacy of an IGF1R kinase inhibitor in this setting. Methods We analyzed transcriptomic data from two independent bladder cancer datasets, corresponding to 200 tumoral and five normal urothelium samples. We evaluated the activation status of the IGF pathway in bladder tumors, by assessing IGF1R phosphorylation and evaluating its correlation with mRNA levels for IGF pathway components. We finally evaluated the correlation between inhibition of proliferation by a selective inhibitor of the IGF1R kinase (AEW541), reported in 13 bladder cancer derived cell lines by the Cancer Cell Line Encyclopedia Consortium and mRNA levels for IGF pathway components. Results IGF1R expression and activation were stronger in non-muscle-invasive than in muscle-invasive bladder tumors. There was a significant inverse correlation between IGF1R phosphorylation and IGFBP5 expression in tumors. Consistent with this finding, the inhibition of bladder cell line viability by IGF1R inhibitor was also inversely correlated with IGFBP5 expression. Conclusion The IGF pathway is activated and therefore a potential therapeutic target for non muscle-invasive bladder tumors and IGFBP5 could be used as a surrogate marker for predicting tumor sensitivity to anti-IGF therapy.

Deficiency of pregnancy-associated plasma protein-A2 (PAPP-A2), an IGF-1 availability regulator, causes postnatal growth failure and dysregulation of bone size and density. The present study aimed to determine the effects of recombinant murine IGF-1 (rmIGF-1) on bone composition and remodeling in constitutive Pappa2 knock-out (ko/ko) mice. To address this challenge, X-ray diffraction (XRD), attenuated total reflection-fourier transform infra-red (ATR-FTIR) spectroscopy and gene expression analysis of members of the IGF-1 system and bone resorption/formation were performed. Pappa2ko/ko mice (both sexes) had reduced body and bone length. Male Pappa2ko/ko mice had specific alterations in bone composition (mineral-to-matrix ratio, carbonate substitution and mineral crystallinity), but not in bone remodeling. In contrast, decreases in collagen maturity and increases in Igfbp3, osteopontin (resorption) and osteocalcin (formation) characterized the bone of Pappa2ko/ko females. A single rmIGF-1 administration (0.3 mg/kg) induced short-term changes in bone composition in Pappa2ko/ko mice (both sexes). rmIGF-1 treatment in Pappa2ko/ko females also increased collagen maturity, and Igfbp3, Igfbp5, Col1a1 and osteopontin expression. In summary, acute IGF-1 treatment modifies bone composition and local IGF-1 response to bone remodeling in mice with Pappa2 deficiency. These effects depend on sex and provide important insights into potential IGF-1 therapy for growth failure and bone loss and repair.

Insulin-like growth factor-1 (IGF-1) is the principal mediator of growth hormone (GH), plays a crucial role in promoting cell growth and differentiation in childhood and continues to have an anabolic effect in adults. IGF-1 is part of a wide network of growth factors, receptors and binding proteins involved in mediating cellular proliferation, differentiation and apoptosis. Bioavailability of IGF-1 is affected by insulin-like growth factor binding proteins (IGFBPs) which bind IGF-1 in circulation with an affinity equal to or greater than that of the IGF-1 receptor (IGF-1R). The six IGFBPs serve as carrier proteins and bind approximately 98% of all circulating IGF-1. Other proteins known to bind IGF-1 include ten IGFBP-related proteins (IGFBP-rPs), albeit with lower affinities than the IGFBPs. IGF-1 expression levels vary in a number of clinical conditions suggesting it has the potential to provide crucial information as to the state of an individual’s health. IGF-1 is also a popular doping agent in sport and has featured in many high-profile doping cases in recent years. However, the existence of IGFBPs significantly reduces the levels of immunoreactive IGF-1 in samples, requiring multiple pre-treatment steps that reduce reproducibility and complicates interpretation of IGF-1 assay results. Here we provide an overview of the IGF network of growth factors, their receptors and the entirety of the extended family of IGFBPs, IGFBP-rPs, E peptides as well as recombinant IGF-1 and their derivatives. We also discuss issues related to the detection and quantification of bioavailable IGF-1.

To understand the carbohydrate utilization ability during developmental stages of Clarias magur , the mRNA levels and enzyme activity of amylase were studied. Furthermore, the transcript levels of some important growth genes like growth hormone (GH), insulin-like growth factor I (IGF-I) and insulin-like growth factor binding protein (IGFBP) were evaluated. The enzymatic activity and mRNA expression of alpha-amylase along with expression of growth-related genes were examined from hatching until 34 days post-hatching (dph) by quantitative reverse transcription-polymerase chain reaction (qRT-PCR). Subsequently, mRNA expression pattern revealed the significantly (P <.05) high transcript level of alpha-amylase during early stages and early peaks were found at 3 to 6 dph, later the expression decreased till the end of experiment. Growth-related genes like GH , IGF-I and IGFBP showed a variable level of mRNA expression pattern from 0 dph to 34 dph. However, there was no significant difference (P >.05) in the mRNA expression of growth-related genes among the different time points of the present study. Moreover, the amylase activity revealed almost same pattern as that of its mRNA expression. In general, the present results suggested that C. magur has the ability to utilize the digestible carbohydrates during the early stages and can be helpful in developing low cost feeds for larvae. • Ontogenetic development of alpha-amylase was investigated in Clarias magur larvae. • mRNA expression and activity of alpha-amylase was significantly high during initial stages. • C. magur has the ability to utilize digestible carbohydrate during early larval development. • The transcript levels of growth-related genes were insignificant among the selected time points. [ABSTRACT FROM AUTHOR]

• The IGFBP family have been shown to have both IGF dependent and independent actions in angiogenesis, and may be stimulatory or inhibitory. • IGFBP-1 and IGFBP-2 have consistent pro-angiogenic effects that could potentially be exploited in the future for therapeutic angiogenesis during ischemic insult. • IGFBP-3 and IGFBP-7 appear to have both pro and anti-angiogenic properties dependent on the cellular environment. • IGFBP-4 and IGFBP-5 have predominantly anti-angiogenic properties, and could provide potential new targets and avenues for research in developing novel cancer therapeutics. Angiogenesis is a tightly regulated activity that is vital during embryonic development and for normal physiological repair processes and reproduction in healthy adults. Pathological angiogenesis is a driving force behind a variety of diseases including cancer and retinopathies, and inhibition of angiogenesis is a therapeutic option that has been the subject of much research, with several inhibitory agents now available for medical therapy. Conversely, therapeutic angiogenesis has been mooted as having significant potential in the treatment of ischemic conditions such as angina pectoris and peripheral arterial disease, but so far there has been less translation from lab to bedside. The insulin-like growth factor binding proteins (IGFBP) are a family of seven proteins essential for the binding and transport of the insulin-like growth factors (IGF). It is being increasingly recognised that IGFBPs have a significant role beyond simply modulating IGF activity, with evidence of both IGF dependent and independent actions through a variety of mechanisms. Moreover, the action of the IGFBPs can be stimulatory or inhibitory depending on the cell type and environment. Specifically the IGFBPs have been heavily implicated in angiogenesis, both pathological and physiological, and they have significant promise as targeted cell therapy agents for both pathological angiogenesis inhibition and therapeutic angiogenesis following ischemic injury. In this short review we will explore the current understanding of the individual impact of each IGFBP on angiogenesis, and the pathways through which these effects occur. [ABSTRACT FROM AUTHOR]

Regular physical activity not only improves the exercise capacity of the skeletal muscle performing the contractions, but it is beneficial for the whole body. An extensive search for "exercise factors" mediating these beneficial effects has been going on for decades. Particularly skeletal muscle tissue has been investigated as a source of circulating exercise factors, and several myokines have been identified. However, exercise also has an impact on other tissues. The liver is interposed between energy storing and energy utilising tissues and is highly active during exercise, maintaining energy homeostasis. Recently, a novel group of exercise factors—termed hepatokines—has emerged. These proteins (fibroblast growth factor 21, follistatin, angiopoietin-like protein 4, heat shock protein 72, insulin-like growth factor binding protein 1) are released from the liver and increased in the bloodstream during or in the recovery after an exercise bout. In this narrative review, we evaluate this new group of exercise factors focusing on the regulation and potential function in exercise metabolism and adaptations. These hepatokines may convey some of the beneficial whole-body effects of exercise that could ameliorate metabolic diseases, such as obesity or type 2 diabetes. [ABSTRACT FROM AUTHOR]

Insulin-like growth factor-1 (IGF-1) and its binding proteins have been implicated in the pathophysiology of coronary artery disease (CAD) and myocardial infarction (MI). We investigated components of the IGF-1 system in circulation at the time of acute MI and following reperfusion in relation to levels of stable CAD patients and controls. Patients with MI (MI Group, n=31) treated with percutaneous coronary intervention (PCI) were compared to patients with stable CAD subjected to scheduled PCI (CAD Group, n=40) and controls with symptoms mimicking CAD without stenosis in angiography (Control Group, n=43). The number and extent of stenosis were recorded. Total and free IGF-1, total and intact IGF binding protein (IGFBP)-3 and -4, pico-Pregnancy Associated Plasma Protein-A (PAPP-A), and the known markers ALT, AST, CK and CK-MB were measured at baseline and 6 or 24 h after the intervention. Patients with MI had higher free IGF-1 (p=0.003) and PAPP-A (p=0.011), but lower intact IGFBP-4 (p=0.006) compared with patients with stable CAD or healthy controls. None of the investigated molecules changed following reperfusion or correlated with the extent of stenosis. AST (p<0.001), CK (p<0.001) and CK-MB (p<0.001), were also higher. Free IGF-1, intact IGFBP-4 and PAPP-A could predict MI, but with lower accuracy than CK-MB. In conclusion, free IGF-1 levels are higher in MI compared to CAD patients and controls and this could result from increased cleavage of its binding protein IGFBP-4 by the higher PAPP-A levels. Free IGF-1, intact IGFBP-4, and/or PAPP-A are inferior to CK-MB as predictors or markers of myocardial damage. [ABSTRACT FROM AUTHOR]

Abstract Objective In humans, loss-of-function mutations in the gene encoding pregnancy-associated pregnancy protein-A2 cause short stature and slightly reduced bone density. The goal of this study was to determine the effects of Pappa2 deletion on bone in mice. Design Pappa2 deletion mice and littermate controls were culled at 10, 19 or 30 weeks of age and femurs were analysed by micro-computed tomography. Serum markers of bone turnover and insulin-like growth factor binding protein 5 (IGFBP-5), a proteolytic target of PAPP-A2, were measured by ELISA. Results At 10 and 19 weeks of age, Pappa2 deletion mice had slightly reduced trabecular parameters, but by 19 weeks of age, female deletion mice had increased cortical tissue mineral density, and this trait was increased by a small amount in deletion mice of both sexes at 30 weeks. Cortical area fraction was increased in Pappa2 deletion mice at all ages. Deletion of Pappa2 increased circulating IGFBP-5 levels and reduced markers of bone turnover (PINP and TRACP 5b). Conclusions PAPP-A2 contributes to the regulation of bone structure and mass in mice, likely through control of IGFBP-5 levels. The net effect of changes in bone formation and resorption depend on sex and age, and differ between trabecular and cortical bone. Highlights • Pappa2 deletion in mice reduced markers of bone turnover. • Trabecular measures were reduced in both sexes at 10 weeks and in males at 19 weeks. • Cortical tissue mineral density was increased in an age- and sex-dependent manner. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • Individual phenolic compounds (IPCs) and polyphenol-rich extracts (PREs) are natural source of chemoprevention agents. • The IPCs and PREs inhibit the activity and expression of IGF-1 and IGF-1R in vitro and in vivo. • The IPCs and PREs up-regulate the expression of serum IGFBP-3. • The IPCs and PREs demonstrate high anti-proliferation and pro-apoptotic potential. Abstract Plant polyphenols, including polyphenol-rich extracts, display various biological activities. They have been found to act as, among others, anti-oxidative, anti-proliferative, pro-apoptotic, anti-angiogenic and anti-inflammatory agents. These compounds can modulate the activities of some functional proteins and receptors, such as insulin-like growth factor system, including IGF, IGF-1R, and IGFBPs proteins. The IGF system plays an important role in cell processes such as proliferation, differentiation and apoptosis, as well as in carcinogenesis. Plant polyphenols also have the ability to prevent the development of cancer, modulating some of the signal transduction pathways (PI3K/Akt and MAPK/ERK) associated with the process. Their variety of mechanisms of action offers hope that both individual phenolic compounds and extracts may be used for the prevention or inhibition of carcinogenesis. This review discusses the impact of natural polyphenols and polyphenol-rich extracts on the expression and activity of IGF-1, IGF-R, and IGFBP in various cancers. [ABSTRACT FROM AUTHOR]

Rainbow trout with gene editing-induced reductions in serum insulin-like growth factor binding protein (IGFBP)-2b exhibit similar growth performance compared to fish without IGFBP-2b gene disruption. The objective of this study is to determine how the components of the insulin-like growth factor (IGF)/IGFBP system respond to a reduction in serum IGFBP-2b abundance. Editing the IGFBP-2b genes in rainbow trout resulted in an 83% decrease in serum IGFBP-2b in mutants. This resulted in a 35% reduction in serum IGF-I, which was offset by reduced expression of hepatic igfbp-1a2 and increased muscle igfr-1a; these responses suggest that an increased IGF-I signaling capacity offset reductions in serum IGF-I. During feed deprivation, the differential expression of igfbp genes supports the attenuation of the growth inhibitory response, likely due to the further reduction in serum IGF-I that alleviated the need for an IGF-inhibitory response. Unique igfbp expression patterns occurred during refeeding, suggesting an enhanced IGF-I signaling capacity in controls. Collectively, these findings support that the role of IGFBP-2b is to regulate serum IGF-I concentrations. The compensatory regulation of IGF/IGFBP system genes indicates that adjustments in other IGFBP, both circulating and at the local level, maintain IGF-I signaling at a level appropriate for the nutritional state of the fish.