Expression Of Insulin-like Growth Factor Research Articles

Improved growth and immunity in Nile tilapia Oreochromis niloticus fed a fermented rice bran supplement

Improvement of growth performance and disease resistance of cultured species is an important objective of the aquaculture industry. In this study, solid-state fermentation (SSF) was applied for increasing the nutritional value of rice bran with baker's yeast (Saccharomyces cerevisiae). Four diets containing different levels of fermented rice bran (FRB) at 0, 100, 200 and 300 g/kg (FRB0, FRB10, FRB20 and FRB30, respectively) were tested using juvenile Nile tilapia Oreochromis niloticus (average body weight = 5.22±0.02 g) for 56 days. Compared to FRB0, all diets improved growth performance of the experimental fish (P<0.05). Intestinal amylase and protease amounts were significantly increased (P<0.05). The experimental fish were intraperitoneally injected with Streptococcus agalactiae and the cumulative mortality rate was monitored for 10 days. All FRB-supplemented diets resulted in greater survival rates in challenge fish. The FRB20 and FRB30 diets promoted expression of insulin-like growth factor I (IGF-I) transcripts and enhanced non-specific immunity; lysozyme and antioxidant enzyme activities; myeloperoxidase (MPO), catalase (CAT), and superoxide dismutase (SOD) (P<0.05). The expression level of interleukin 8 (IL-8) was down-regulated in fish fed FRB20 and FRB30 (P<0.05) but IL-10 was up-regulated in fish fed FRB10 and FRB30 (P<0.05) while IL-1β was up-regulated in fish fed FRB20 (P<0.05). The expression of complementary 3 (C3) transcripts was significantly increased while nuclear factor-kappa B (NF-κB) was decreased in fish fed all FRB-supplemented diets (P<0.05). Conventional histology revealed increased villus height following FRB30 treatment (P<0.05). These results suggest the beneficial use of FRB supplementation on growth, immune defense and stress tolerance for juvenile O. niloticus.

Late-gestation maternal undernutrition induces circulatory redistribution while preserving uteroplacental function independent of fetal glycaemic state.

Programming effects of maternal undernutrition on fetal metabolic and cardiovascular systems are well elucidated, yet a detailed characterization of maternal haemodynamics is not available. This study used comprehensive cardiovascular magnetic resonance (CMR) imaging to quantify maternal haemodynamics after 29days (111-140 days) of late-gestation undernutrition (LGUN) in pregnant sheep. Control ewes received 100% of metabolizable energy requirements (MERs, n=15), whereas LGUN ewes were globally nutrient restricted to 50% MER (n=18), with a subset of fetuses undergoing continuous glucose infusion (LGUN+G, n=6/18). Ewes underwent CMR (138-140 days' gestation), and placental tissue was collected the next day. Ewes in both LGUN groups had reduced body weight and mean blood glucose concentration across gestation. Ventricular dimensions were lower in both LGUN groups. Uterine artery blood flow (QUtA) was elevated in the LGUN group compared with controls, whereas peripheral blood flow was reduced and further diminished in LGUN+G. Maternal weight change correlated with all haemodynamic parameters across all groups. Uteroplacental oxygen and glucose delivery were increased in LGUN compared to control ewes, whereas uteroplacental oxygen consumption was preserved. LGUN did not impact placental or fetal weight, and markers of brain-sparing physiology were absent. Placental expression of insulin-like growth factors (IGF-1 and IGF-2) and their receptors, glucose, fatty acid (FA) or amino acid transporters and markers of angiogenesis was not impacted. FA transporter expression was positively correlated with QUtA, and FA binding protein correlated negatively with maternal weight change. Maternal cardiovascular adaptations in response to LGUN manifest as preservation of placental growth and function, thereby preserving fetal growth. KEY POINTS: Maternal undernutrition during pregnancy alters fetal metabolic and cardiovascular physiology, but little is known about alterations in maternal haemodynamics. Late-gestation undernutrition (LGUN) and LGUN+G redirected maternal blood flow from the periphery to the uteroplacental unit, concomitantly increasing the delivery of glucose and oxygen to the uteroplacental unit. Substrate transporter expression and uteroplacental oxygen consumption were preserved in LGUN and LGUN+G, suggesting prioritization of the placenta. This study is the first to report detailed maternal haemodynamics in the setting of maternal undernutrition, where placental growth and function were maintained, ultimately preserving fetal oxygen metabolism and growth.

Characterization of a novel IGFBP-2 transcript in the ovarian granulosa cells of chicken follicles: mRNA expression, function and effect of reproductive hormones and IGF1

Insulin-like growth factor binding protein-2 (IGFBP-2), a binding protein of insulin-like growth factor (IGF) system, regulates the activity of IGFs and also influences cellular function with endogenous activity. In mammals, IGFBP-2 is reported to affect ovarian follicle development and steroidogenesis; however, its role in the chicken ovary is unknown. In this study, we investigated the mRNA expression and function of a novel IGFBP-2 transcript and the effect of reproductive hormones and insulin-like growth factor 1 (IGF1) on its expression in the ovarian granulosa cells of chicken follicles. The mRNA expression of IGFBP-2 was significantly increased in granulosa cells after follicle selection and was higher in hierarchical granulosa cells (Post-GCs) than in pre-hierarchical granulosa cells (Pre-GCs). IGFBP-2 promoted the proliferation and inhibited the apoptosis of both Pre-GCs and Post-GCs, enhanced the mRNA expression of genes involved in progesterone (P4) synthesis in Pre-GCs. However, in Post-GCs, IGFBP-2 inhibited the mRNA expression of these genes and suppressed P4 secretion. The mRNA expression of IGFBP-2 was inhibited by estradiol (E2) and follicle-stimulating hormone (FSH), but enhanced by P4 in Pre-GCs. In Post-GCs, FSH and IGF1 stimulated the mRNA expression of IGFBP-2 synergistically. Knockdown of IGFBP-2 attenuated the stimulatory effect of IGF1 on the mRNA expression of the side chain cleavage enzyme cytochrome P450 family 11 subfamily A member 1 (CYP11A1). These findings indicate that IGFBP-2 is regulated by FSH and IGF1, exerts different functions in Pre-GCs and Post-GCs in regulating IGF1 and plays an important role in chicken follicle development by affecting granulosa cell proliferation and P4 synthesis.

IGF-1 impacts neocortical interneuron connectivity in epileptic spasm generation and resolution

Little is known about the mechanisms that generate epileptic spasms following perinatal brain injury. Recent studies have implicated reduced levels of Insulin-like Growth Factor 1 (IGF-1) in these patients’ brains. Other studies have reported low levels of the inhibitory neurotransmitter, GABA. In the TTX brain injury model of epileptic spasms, we undertook experiments to evaluate the impact of IGF-1 deficiencies on neocortical interneurons and their role in spasms. Quantitative immunohistochemical analyses revealed that neocortical interneurons that express glutamic acid decarboxylase, parvalbumin, or synaptotagmin 2 co-express IGF-1. In epileptic rats, expression of these three interneuron markers were reduced in the neocortex. IGF-1 expression was also reduced, but surprisingly this loss was confined to interneurons. Interneuron connectivity was reduced in tandem with IGF-1 deficiencies. Similar changes were observed in surgically resected neocortex from infantile epileptic spasms syndrome (IESS) patients. To evaluate the impact of IGF-1 deficiencies on interneuron development, IGF-1R levels were reduced in the neocortex of neonatal conditional IGF-1R knock out mice by viral injections. Four weeks later, this experimental maneuver resulted in similar reductions in interneuron connectivity. Treatment with the IGF-1 derived tripeptide, (1–3)IGF-1, abolished epileptic spasms in most animals, rescued interneuron connectivity, and restored neocortical levels of IGF-1. Our results implicate interneuron IGF-1 deficiencies, possibly impaired autocrine IGF-1 signaling and a resultant interneuron dysmaturation in epileptic spasm generation. By restoring IGF-1 levels, (1–3)IGF-1 likely suppresses spasms by rescuing interneuron connectivity. Results point to (1–3)IGF-1 and its analogues as potential novel disease-modifying therapies for this neurodevelopmental disorder.

IGF2BP3/CTCF Axis-Dependent NT5DC2 Promotes M2 Macrophage Polarization to Enhance the Malignant Progression of Lung Squamous Cell Carcinomas.

Lung squamous cell carcinoma (LUSC) is a type of lung cancer that develops in the squamous cells. It is known to be promoted by the activation of various signaling pathways and the dysregulation of key regulatory molecules. One such molecule, 5'-nucleotidase domain containing 2 (NT5DC2), has been identified as a critical regulator in various cancers including lung cancer. However, there are no data regarding its role in LUSC. The mRNA expression of insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3), CCCTC-binding factor (CTCF), and NT5DC2 was analyzed using quantitative real-time polymerase chain reaction (qRT-PCR), whereas their protein expression was assessed using a western blotting assay. Cell proliferation was determined using a cell counting kit-8 (CCK-8) assay. Cell apoptosis, CD11b expression, and CD206 expression were analyzed using flow cytometry. Tube formation was assessed through a tube formation assay. Glucose consumption, lactate production, and ATP levels were measured using colorimetric methods. The effect of NT5DC2 on the malignant progression of LUSC cells was analyzed using a xenograft mouse model assay. The levels of transforming growth factor-beta 1 (TGF-β1) and interleukin-10 (IL-10) were detected using enzyme-linked immunosorbent assays. The associations among IGF2BP3, CTCF and NT5DC2 were identified using dual-luciferase reporter assay, RNA immunoprecipitation assay and m6A RNA immunoprecipitation assay. The expression of NT5DC2 was found to be upregulated in LUSC tissues and cells when compared with normal lung tissues and normal human bronchial epithelial cells. Silencing of NT5DC2 inhibited LUSC cell proliferation, tube formation, glycolysis, M2 macrophage polarization, and tumor formation while inducing cell apoptosis. In addition, CTCF was found to transcriptionally activate NT5DC2 in LUSC cells. IGF2BP3 stabilized the mRNA expression of CTCF through m6A methylation. Further, overexpression of CTCF or NT5DC2 attenuated the effects of IGF2BP3 silencing in both NCI-520 and SK-MES-1 cells. The IGF2BP3/CTCF axis-dependent NT5DC2 promotes M2 macrophage polarization, thereby enhancing the malignant progression of LUSC. This study was the first to reveal the role of NT5DC2 in LUSC and the underlying mechanism. The result suggests that targeting the IGF2BP3/CTCF/NT5DC2 axis may have clinical significance in the treatment of LUSC.

Swimming training promotes angiogenesis of endothelial progenitor cells by upregulating IGF1 expression and activating the PI3K/AKT pathway in type 2 diabetic rats.

The present study aimed to investigate the effect of swimming training on the angiogenesis of endothelial progenitor cells (EPCs) in type 2 diabetes mellitus (T2DM) rats by upregulating the insulin‑like growth factor 1 (IGF1) expression and to reveal its potential mechanism of action. Male Sprague‑Dawley rats were divided into the Control, Model, Model train, Model train + short interfering (si)‑NC and Model train + si‑IGF1 groups. Serum glucose levels were measured using the oral glucose tolerance test. EPCs were isolated from the bone marrow cavity and identified through morphological observation and immunofluorescence staining. The expression of IGF‑1 mRNA in rat serum and EPCs was analyzed by reverse transcription‑quantitative PCR. The fasting insulin levels in serum were assessed by ELISA. Cell Counting Kit‑8, scratch assay and tube formation assay were used to determine the cell viability, migration and tube formation of rat EPCs, and western blotting was employed to measure the expression levels of IGF1, phosphoinositide 3‑kinase (PI3K), phosphorylated‑PI3K, protein kinase B (AKT) and phosphorylated‑AKT. The present study demonstrated that swimming training significantly decreased the glucose levels and homeostatic model assessment of insulin resistance scores, but increased the fasting insulin levels and IGF1 mRNA expression. Microscopic observation and immunofluorescence identification suggested that EPCs were successfully isolated. In addition, swimming training markedly elevated the levels of IGF1 and promoted cell viability, migration and tube formation in rat EPCs. Furthermore, IGF1 knockdown experiments indicated that swimming training might play a regulatory role by elevating the IGF1 expression to activate the PI3K/AKT pathway. Overall, swimming training promoted the angiogenesis of EPCs in T2DM rats and its potential mechanism may be related to the upregulation of IGF1 expression and the activation of the PI3K/AKT pathway.

A microparticle delivery system for extended release of all-trans retinoic acid and its impact on macrophage insulin-like growth factor 1 release and myotube formation

Muscle atrophy secondary to disuse, aging, or illness increases the risk of injury, prolonged recovery, and permanent disability. The recovery process involves macrophages and their secretions, such as insulin-like growth factor 1 (IGF-1), which direct muscle to regenerate and grow. Retinoic acid receptor (RAR) activation in macrophages increases IGF-1 expression and can be achieved with all-trans retinoic acid (ATRA). However, poor bioavailability limits its clinical application. Thus, we encapsulated ATRA into poly(lactide-co-glycolide) microparticles (ATRA-PLG) to maintain bioactivity and achieve extended release. ATRA-PLG induces IGF-1 release by RAW 264.7 macrophages, and conditioned media from these cells enhances C2C12 myotube formation through IGF-1. Additionally, ATRA released from ATRA-PLG enhances myotube formation in the absence of macrophages. Toward clinical translation, we envision that ATRA-PLG will be injected in the vicinity of debilitated muscle where it can be taken up by macrophages and induce IGF-1 release over a predetermined therapeutic window. Along these lines, we demonstrate that ATRA-PLG microparticles are readily taken up by bone marrow-derived macrophages and reside within the cytosol for at least 12 days with no toxicity. Interestingly, ATRA-PLG induced IGF-1 secretion by thioglycolate-elicited macrophages, but not bone marrow derived macrophages. We found that the RAR isoforms present in lysate differed between the macrophages studied, which could explain the different IGF-1 responses to ATRA. Given that ATRA-PLG enhances myotube formation directly (through ATRA) and indirectly (through macrophage IGF-1) this study supports the further testing of this promising pharmaceutical using rodent models of muscle regeneration and growth.

COMPARISON OF IMMUNOHISTOCHEMICAL EXPRESSION OF INSULIN LIKE GROWTH FACTOR 1 RECEPTOR (IGF-1R) IN BENIGN AND MALIGNANT SALIVARY GLAND TUMORS

Objectives: To evaluate the difference in immunohistochemical expression of insulin-like growth factor-1 receptor (IGF-1R) in diagnosed cases of benign and malignant salivary gland tumors.Materials and Methods: This Comparative Cross-Sectional Study was conducted at the department of Pathology, Peshawar Medical and Dental College, Peshawar. A total of 100 Salivary Gland Tumors from 56 male and 44 female patients were included in the study, with an average age of 43.50 ± 15.21. The Immunohistochemical Expression of Insulin-like Growth Factor 1 Receptor was determined on both benign and malignant salivary gland tumors using the Bio SB Polyclonal IGF-1R antibody (rabbit, BT-AP04398). The collected data were analyzed using SPSS version 25.Results: For the immunohistochemical expression of IGF-1R on benign and malignant salivary gland tumors, the Allred Scoring method was utilized. P value of &lt;0.05 was considered significant, but no positive signifi cance was found between the expression of IGF-1R and salivary gland tumors.Conclusion: IGF1R expression was positive in various SGTs but no statistically significant difference was seen in multiple histopathological types of benign and malignant SGT

Androgen-mediated maternal effects and trade-offs: postnatal hormone development, growth, and survivorship in wild meerkats.

Mammalian reproductive and somatic development is regulated by steroid hormones, growth hormone (GH), and insulin-like growth factor-1 (IGF-1). Based largely on information from humans, model organisms, and domesticated animals, testosterone (T) and the GH/IGF-1 system activate sexually differentiated development, promoting male-biased growth, often at a cost to health and survivorship. To test if augmented prenatal androgen exposure in females produces similar developmental patterns and trade-offs, we examine maternal effects in wild meerkats (Suricata suricatta), a non-model species in which adult females naturally, albeit differentially by status, express exceptionally high androgen concentrations, particularly during pregnancy. In this cooperative breeder, the early growth of daughters predicts future breeding status and reproductive success. We examine effects of normative and experimentally induced variation in maternal androgens on the ontogenetic patterns in offspring reproductive hormones (androstenedione, A4; T; estradiol, E2), IGF-1, growth from pup emergence at 1 month to puberty at 1 year, and survivorship. Specifically, we compare the male and female offspring of dominant control (DC or high-T), subordinate control (SC or lower-T), and dominant treated (DT or blocked-T) dams, the latter having experienced antiandrogen treatment in late gestation. Meerkat offspring showed sex differences in absolute T and IGF-1 concentrations, developmental rates of A4 and E2 expression, and survivorship - effects that were sometimes socially or environmentally modulated. Atypical for mammals were the early male bias in T that disappeared by puberty, the absence of sex differences in A4 and E2, and the female bias in IGF-1. Food availability was linked to steroid concentrations in females and to IGF-1, potentially growth, and survival in both sexes. Maternal treatment significantly affected rates of T, E2, and IGF-1 expression, and weight, with marginal effects on survivorship; offspring of DT dams showed peak IGF-1 concentrations and the best survivorship. Maternal effects thus impact offspring development in meerkats, with associated trade-offs: Whereas prenatal androgens modify postnatal reproductive and somatic physiology, benefits associated with enhanced competitiveness in DC lineages may have initial costs of reduced IGF-1, delay in weight gain, and decreased survivorship. These novel data further confirm the different evolutionary and mechanistic pathways to cooperative breeding and call for greater consideration of natural endocrine variation in both sexes.

The androgen receptor in mesenchymal progenitors regulates skeletal muscle mass via Igf1 expression in male mice

Androgens exert their effects primarily by binding to the androgen receptor (AR), a ligand-dependent nuclear receptor. While androgens have anabolic effects on skeletal muscle, previous studies reported that AR functions in myofibers to regulate skeletal muscle quality, rather than skeletal muscle mass. Therefore, the anabolic effects of androgens are exerted via nonmyofiber cells. In this context, the cellular and molecular mechanisms of AR in mesenchymal progenitors, which play a crucial role in maintaining skeletal muscle homeostasis, remain largely unknown. In this study, we demonstrated expression of AR in mesenchymal progenitors and found that targeted AR ablation in mesenchymal progenitors reduced limb muscle mass in mature adult, but not young or aged, male mice, although fatty infiltration of muscle was not affected. The absence of AR in mesenchymal progenitors led to remarkable perineal muscle hypotrophy, regardless of age, due to abnormal regulation of transcripts associated with cell death and extracellular matrix organization. Additionally, we revealed that AR in mesenchymal progenitors regulates the expression of insulin-like growth factor 1 (Igf1) and that IGF1 administration prevents perineal muscle atrophy in a paracrine manner. These findings indicate that the anabolic effects of androgens regulate skeletal muscle mass via, at least in part, AR signaling in mesenchymal progenitors.

Altered expression of insulin-like growth factor 2 mRNA binding protein 2 is associated with periodontal disease- a case-control analysis

Background/PurposePeriodontitis has a multifactorial pathogenesis involving genetic and epigenetic factors. Insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) is an N6-methyladenosine (m6A) reader that enhances messenger RNA (mRNA) stability in an m6A-dependent manner. It is being considered as a potential target for treating inflammatory diseases. However, its role in periodontitis and its specific target genes affected by m6A modification are not yet well understood. This study aims to investigate the expression of IGF2BP2 and its potential involvement in periodontitis. Materials and methodsSeventy participants were recruited, including 35 patients with periodontitis and 35 healthy controls. Clinical examination and radiography were performed to confirm a diagnosis of periodontitis. Gingival tissue samples were collected from each participant, and IGF2BP2 expression was measured using real-time PCR and western blotting. In addition, in silico tools were used to identify the IGF2BP2 network pathway and its functions. ResultsIGF2BP2 expression was significantly higher in the periodontitis group than in the healthy control group (p < 0.0001). Functional enrichment analysis revealed that the IGF2BP2 pathway network plays a crucial role in periodontal pathogenesis. In addition, pro-inflammatory cytokines, including IL-1β and IL-6, were significantly increased in the periodontitis group (p < 0.0001) and were positively correlated with IGF2BP2 expression and m6A methylation sites. ConclusionOur study demonstrated that increased IGF2BP2 expression is associated with periodontitis, which may regulate proinflammatory cytokine production in an m6A-dependent manner. Further functional studies are required to understand the mechanism of action of IGF2BP2 in periodontitis.

LONP1 alleviates ageing-related renal fibrosis by maintaining mitochondrial homeostasis.

Mitochondrial dysfunction is a pivotal event contributing to the development of ageing-related kidney disorders. Lon protease 1 (LONP1) has been reported to be responsible for ageing-related renal fibrosis; however, the underlying mechanism(s) of LONP1-driven kidney ageing with respect to mitochondrial disturbances remains to be further explored. The level of LONP1 was tested in the kidneys of aged humans and mice. Renal fibrosis and mitochondrial quality control were confirmed in the kidneys of aged mice. Effects of LONP1 silencing or overexpression on renal fibrosis and mitochondrial quality control were explored. In addition, N6-methyladenosine (m6A) modification and methyltransferase like 3 (METTL3) levels, the relationship between LONP1 and METTL3, and the impacts of METTL3 overexpression on mitochondrial functions were confirmed. Furthermore, the expression of insulin-like growth factor 2 mRNA binding protein 2 (IGF2BP2) and the regulatory effects of IGF2BP2 on LONP1 were confirmed invitro. LONP1 expression was reduced in the kidneys of aged humans and mice, accompanied by renal fibrosis and mitochondrial dysregulation. Overexpression of LONP1 alleviated renal fibrosis and maintained mitochondrial homeostasis, while silencing of LONP1 had the opposite effect. Impaired METTL3-m6A signalling contributed at least in part to ageing-induced LONP1 modification, reducing subsequent degradation in an IGF2BP2-dependent manner. Moreover, METTL3 overexpression alleviated proximal tubule cell injury, preserved mitochondrial stability, inhibited LONP1 degradation, and protected mitochondrial functions. LONP1 mediates mitochondrial function in kidney ageing and that targeting LONP1 may be a potential therapeutic strategy for improving ageing-related renal fibrosis.

The relationship between the expression of fibroblast growth factor 19 and insulin-like growth factor 1 in colorectal polyp tissues and the occurrence of colorectal adenomas

Objective: This investigation sought to delineate the associations among colorectal adenomatous polyps, diabetes, and biomolecules involved in glucose metabolism. Method: Data were collected from 40 patients who underwent endoscopic polypectomy at the Endoscopy Department of Shandong Cancer Hospital between June 2019 and September 2021. This cohort included 27 patients with inflammatory polyps and 13 with adenomatous polyps. We assessed fasting insulin (Fins), fasting blood glucose (FBG), and the mRNA expressions of fibroblast growth factor 19 (FGF-19) and insulin-like growth factor 1 (IGF-1) in the polyp tissues. Both univariate and multivariate logistic regression analyses were employed to ascertain the determinants influencing the emergence of adenomatous polyps. From these analyses, a predictive nomogram was constructed to forecast the occurrence of adenomatous polyps, and evaluations on the discriminative capacity, calibration, and clinical utility of the model were conducted. Results: The adenomatous polyp group exhibited markedly elevated levels of glucose, insulin, FGF-19, and IGF-1, with respective concentrations of (8.67±2.70) mmol/L, (12.72±7.69) μU/L, 2.20±1.88, and 1.36±0.69. These figures were significantly higher compared to the inflammatory polyp group, which showed levels of (5.51±0.72) mmol/L, (5.49±2.68) μU/L, 0.53±0.97, and 0.41±0.46, respectively, P=0.001. Multivariate logistic regression revealed that the relative expression of IGF-1 served as an independent risk factor for the development of colorectal adenomatous polyps (OR=5.622, 95% CI:1.085-29.126). The nomogram displayed a C-index of 0.849, indicating substantial discriminative capability. The calibration curve affirmed the model's accuracy in aligning predicted probabilities with actual outcomes, and the clinical decision curve demonstrated thepractical clinical applicability of the model. Conclusions: There was a significant correlation between the occurrence of colorectal adenomatous polyps and glucose metabolic pathways. Individuals with diabetes showed a higher propensity to develop such polyps.

Insulin-like growth factor 2 targets IGF1R signaling transduction to facilitate metastasis and imatinib resistance in gastrointestinal stromal tumors

BACKGROUND Gastrointestinal stromal tumors (GISTs) are typical gastrointestinal tract neoplasms. Imatinib is the first-line therapy for GIST patients. Drug resistance limits the long-term effectiveness of imatinib. The regulatory effect of insulin-like growth factor 2 (IGF2) has been confirmed in various cancers and is related to resistance to chemotherapy and a worse prognosis. AIM To further investigate the mechanism of IGF2 specific to GISTs. METHODS IGF2 was screened and analyzed using Gene Expression Omnibus (GEO: GSE225819) data. After IGF2 knockdown or overexpression by transfection, the phenotypes (proliferation, migration, invasion, apoptosis) of GIST cells were characterized by cell counting kit 8, Transwell, and flow cytometry assays. We used western blotting to evaluate pathway-associated and epithelial-mesenchymal transition (EMT)-associated proteins. We injected transfected cells into nude mice to establish a tumor xenograft model and observed the occurrence and metastasis of GIST. RESULTS Data from the GEO indicated that IGF2 expression is high in GISTs, associated with liver metastasis, and closely related to drug resistance. GIST cells with high expression of IGF2 had increased proliferation and migration, invasiveness and EMT. Knockdown of IGF2 significantly inhibited those activities. In addition, OE-IGF2 promoted GIST metastasis in vivo in nude mice. IGF2 activated IGF1R signaling in GIST cells, and IGF2/IGF1R-mediated glycolysis was required for GIST with liver metastasis. GIST cells with IGF2 knockdown were sensitive to imatinib treatment when IGF2 overexpression significantly raised imatinib resistance. Moreover, 2-deoxy-D-glucose (a glycolysis inhibitor) treatment reversed IGF2 overexpression-mediated imatinib resistance in GISTs. CONCLUSION IGF2 targeting of IGF1R signaling inhibited metastasis and decreased imatinib resistance by driving glycolysis in GISTs.

Fibroblast growth-factor 23-Klotho axis is associated with systemic inflammation and myokine profile in children with chronic kidney disease.

Chronic kidney disease is linked to a disturbed fibroblast growth factor-23 (FGF23)-Klotho axis and an imbalance between myostatin and insulin-like growth factor-1 (IGF-1) expression. This cross-sectional study investigates the association of the FGF23-Klotho axis and myokine profile with serum interleukin-6 (IL-6) and their interactions in pediatric patients. Serum calcium, phosphorus, 25-hydroxyvitamin D, parathormone, c-terminal FGF23, a-Klotho, myostatin, follistatin, IGF-1, and IL-6 were measured in 53 patients with GFR < 60ml/min/1,73m2. Myostatin to lean mass (LM) and to IGF-1 ratios were calculated. IL-6 level > 3rd quartile was considered as high. Myostatin, IGF-1, and follistatin were correlated to LM (rs = 0.513, p < 0.001, rs = 0.652, p < 0.001, rs=-0.483, p < 0.001). Myostatin and follistatin were correlated to IGF-1 (rs = 0.340, p = 0.014, rs=-0.385, p = 0.005). Myostatin/LM but not myostatin or myostatin/IGF-1 ratio was significantly higher in CKD 5D patients (p = 0.001,p = 0.844, p = 0.111). Among mineral bone parameters, lnFGF23 was correlated to lnIL-6 (rs = 0.397, p = 0.004) and associated with high IL-6 (OR 1.905, 95% CI 1.023-3.548). Among myokines, myostatin/IGF-1 ratio was correlated to lnIL-6 (rs = 0.395, p = 0.004) and associated with high IL-6 (OR 1.113, 95% CI 1.028-1.205). All associations were adjusted to CKD stage. Myostatin was correlated to lnFGF23 (rs = 0.331, p = 0.025) and myostatin/IGF-1 ratio to lnKlotho (rs=-0.363, p = 0.013), after adjustment for CKD stage, lnIL-6 and other mineral bone parameters. In pediatric CKD, FGF23 and myostatin/IGF-1 ratio are associated with IL-6, indicating a link between systemic inflammation, mineral bone, and myokine disorders. The correlations between myostatin and FGF23 and between myostatin/IGF-1 and Klotho suggest an interaction between mineral bone and muscle metabolism.

Modulation of toxic effects of ammonia on growth, pathology of liver and kidney tissues and relative expression of GH and IGF-1 Genes by CoQ10 Supplementation in Oncorhynchus mykiss.

Reducing the negative impact of environmental and stressful factors is a crucial step in achieving sustainable aquaculture. Therefore, a study was aimed at evaluating the impacts of Coenzyme Q10 (CoQ10) supplementation on growth, relative gene expression of Growth Hormone (GH) and Insulin-like growth factor-1 (IGF-1), liver and kidney histopathology against stress induced by ammonia in Rainbow trout (Oncorhynchus mykiss). The fish were given feed containing different levels of CoQ10 for 8 weeks: Control - CoQ10 0%, G1 - CoQ10 0.1%, G2 - CoQ10 0.5% and G3 - CoQ10 1%. At the end of the experiment, fish were exposed to ammonia stress concentration at 0.6mg/L for 24 h to assess liver and kidney tissue damage. Results showed that there was a significant activity increase in GH and IGF-1 genes due to supplementation with CoQ10 alone (p < 0.05). Gene expression for GH increased about two-fold whereas that for IGF-1 experienced a four-fold upregulation compared to controls (p < 0.05). CoQ10's-related antioxidant effects probably minimized liver and kidney cellular injuries, as significant decreases were observed in ammonia-induced mortality (p < 0.05). In summary, adding CoQ10 to the diet is a potential way to improve fish production through controlling the gene expression of GH and IGF-1, as well as making fish populations more resistant to possible future stress caused by ammonia in intensive or super-intensive aquaculture systems.

Expression and pathogenesis of insulin-like growth factor-1 and insulin-like growth factor binding protein 3 in a mouse model of ulcerative colitis

Background and aimInsulin-like growth factor-1 may be involved in the epithelial-to-mesenchymal transition process. It can mitigate adverse effects when interacting with insulin-like growth factor binding protein 3. This study aimed to explore alterations in the expression of these two factors in the colonic tissue of mice with ulcerative colitis. MethodThis study utilized animal models. Mice were randomly allocated into three distinct groups. Disease activity index assessment was performed first, followed by histological grading of colitis. Protein and mRNA expression levels were determined using Western blotting and RT-qPCR. Immunohistochemical detection was used to determine histochemistry scores. Pearson correlation and SPSS 25.0 software were used for data analysis. ResultsThe findings indicated a reduction in the expression of the two investigated factors as well as in epithelial-to-mesenchymal transition epithelial markers during inflammation, while the expression of noninflammatory factors increased. These effects were notably amplified following treatment. Interestingly, the changes in epithelial-to-mesenchymal transition-inducing factors and mesenchymal markers contradicted this trend. Pearson correlation analysis revealed a correlation between molecular indicators of change and epithelial-to-mesenchymal transition. ConclusionInsulin-like growth factor-1 and insulin-like growth factor binding protein 3 may play a protective role in the development and progression of ulcerative colitis, potentially through their inhibition of the epithelial-to-mesenchymal transition. These factors hold promise as targets for the clinical diagnosis and treatment of ulcerative colitis.

Lin28a forms an RNA-binding complex with Igf2bp3 to regulate m6A-modified stress response genes in stress granules of muscle stem cells.

In the early embryonic stages, Lin-28 homologue A (Lin28a) is highly expressed and declines as the embryo matures. As an RNA-binding protein, Lin28a maintains some adult muscle stem cells (MuSCs) in an embryonic-like state, but its RNA metabolism regulation mechanism remains unclear. BioGPS analysis revealed that Lin28a expression is significantly higher in muscle tissues than in other tissues. Lin28a-positive muscle stem cells (Lin28a+ MuSCs) were sorted from Lin28a-CreERT2; LSL-tdTomato mouse skeletal muscle tissue, which exhibited a higher proliferation rate than the control group. Lin28a-bound transcripts are enriched in various biological processes such as DNA repair, cell cycle, mitochondrial tricarboxylic acid cycle and oxidative stress response. The expression of insulin-like growth factor 2 mRNA-binding protein 3 (Igf2bp3) was markedly elevated in the presence of Lin28a. Co-immunoprecipitation analysis further demonstrated that Lin28a associates with Igf2bp3. Immunofluorescence analyses confirmed that Lin28a, Igf2bp3 and G3bp1 colocalize to form stress granules (SG), and N6-methyladenosine (m6A) modification promotes the formation of Lin28a-SG. Sequencing of the transcriptome and RNAs immunoprecipitated by Lin28a, Igf2bp3 and m6A antibodies in Lin28a+ MuSCs further revealed that Lin28a and Igf2bp3 collaboratively regulate the expression of DNA repair-related genes, including Fancm and Usp1. Lin28a stabilises Igf2bp3, Usp1, and Fancm mRNAs, enhancing DNA repair against oxidative or proteotoxic stress, thus promoting MuSCs self-renewal. Understanding the intricate mechanisms through which Lin28a and Igf2bp3 regulate MuSCs provides a deeper understanding of stem cell self-renewal, with potential implications for regenerative medicine.

Malignant solitary fibrous tumor of the kidney with IGF2 secretion and without hypoglycemia

BackgroundSolitary fibrous tumor (SFT) is a rare fibroblastic mesenchymal tumor that mostly involves the pleura and infrequently involves extra-pleural sites. De novo SFT of the kidney is uncommon, and malignant SFT is extremely rare.Case presentationWe report a case of a 51-year-old man with a large malignant SFT in the left kidney. Pathological examination confirmed the diagnosis of SFT based on typical morphology, nuclear STAT6 expression, and NAB2-STAT6 gene fusion. The malignant subtype was determined by a large tumor size (≥ 15 cm) and high mitotic counts (8/10 high-power fields). KRAS mutation was identified by DNA sequencing. Insulin-like growth factor 2 (IGF2) was diffusely and strongly expressed in tumor cells, however, hypoglycemia was not observed. Hyperglycemia and high adrenocorticotropic hormone (ACTH) concentration were observed one month after surgery. Hormone measurements revealed normal blood cortisol and aldosterone levels, and increased urinary free cortisol level. A pituitary microadenoma was identified using brain magnetic resonance imaging, which may be responsible for the promotion of hyperglycemia.ConclusionsWe report a case of renal malignant SFT with a KRAS mutation, which was previously unreported in SFT and may be associated with its malignant behavior. Additionally, we emphasize that malignant SFT commonly causes severe hypoglycemia due to the production of IGF2. However, this effect may be masked by the presence of other lesions that promote hyperglycemia. Therefore, when encountering a malignant SFT with diffuse and strong IGF2 expression and without hypoglycemia, other lesions promoting hyperglycemia need to be ruled out.

Cardiac programming in the placentally restricted sheep fetus in early gestation.

Fetal growth restriction (FGR) occurs in 8% of human pregnancies, and the growth restricted newborn is at a greater risk of developing heart disease in later adult life. In sheep, experimental restriction of placental growth (PR) from conception results in FGR, a decrease in cardiomyocyte endowment and an upregulation of pathological hypertrophic signalling in the fetal heart in late gestation. However, there is no change in the expression of markers of cellular proliferation nor in the level of cardiomyocyte apoptosis in the heart of the PR fetus in late gestation. This suggests that FGR arises early in gestation and programs a decrease in cardiomyocyte endowment in early, rather than late, gestation. Here, control and PR fetal sheep were humanely killed at 55 days' gestation (term, 150days). Fetal body and heart weight were lower in PR compared with control fetuses and there was evidence of sparing of fetal brain growth. While there was no change in the proportion of cardiomyocytes that were proliferating in the early gestation PR heart, there was an increase in measures of apoptosis, and markers of autophagy and pathological hypertrophy in the PR fetal heart. These changes in early gestation highlight that FGR is associated with evidence of early cell death and compensatory hypertrophic responses of cardiomyocytes in the fetal heart. The data suggest that early placental restriction results in a decrease in the pool of proliferative cardiomyocytes in early gestation, which would limit cardiomyocyte endowment in the heart of the PR fetus in late gestation. KEY POINTS: Placental restriction leading to fetal growth restriction (FGR) and chronic fetal hypoxaemia in sheep results in a decrease in cardiomyocyte endowment in late gestation. FGR did not change cardiomyocyte proliferation during early gestation but did result in increased apoptosis and markers of autophagy in the fetal heart, which may result in the decreased endowment of cardiomyocytes observed in late gestation. FGR in early gestation also results in increased hypoxia inducible factor signalling in the fetal heart, which in turn may result in the altered expression of epigenetic regulators, increased expression of insulin-like growth factor 2 and cardiomyocyte hypertrophy during late gestation and after birth.