Serum insulin-like growth factor-1 as a potential prognostic biomarker for heart failure with reduced ejection fraction: a meta-analysis.

Background: Most studies have indicated that peripheral insulin-like growth levels factor-1 (IGF-1) is valuable in diagnosing heart failure, although the results have been inconsistent. To help solve the debate, we performed a meta-analysis to explore the relationship between IGF-1 and heart failure (HF). Methods: We conducted an extensive search across various databases such as Embase, Cochrane Library, Pubmed, Medline, and Web of Science on May 30, 2023. From the extensive pool of studies, we selected 16 relevant articles, encompassing a total of 1,380 cases and 1,153 controls, to conduct a rigorous meta-analysis. Results: The total results indicated that there is an association between lower IGF-1 level and HF. The random-effects model yielded a pooled standardized mean difference (SMD) of -0.598 (95% CI: -1.081 to -0.116, P = 0.015). Further subgroup analysis also showed that IGF-1 levels were associated with HF in the age difference ≥5 years subgroup and body mass index difference >1 subgroup. Additionally, significant association between IGF-1 levels and HF were detected in the "serum" samples and "Europe" subgroups. Importantly, we observed IGF-1 showed significant lower levels in patients with reduced ejection fraction (HFrEF) compared to the controls, not in patients with preserved ejection fraction (HFpEF). The Begg's and Egger's tests revealed no indication of publication bias. Conclusions: Our meta-analysis has provided evidence suggesting a substantial correlation between reduced levels of IGF-1 and the occurrence of HF. Further prospective studies are necessary to ascertain the use of IGF-1 as a reliable biomarker for diagnosing HF, especially for HFrEF. But the diagnosis of HFpEF should be cautious.

Insulin-like growth factor (IGF) levels in pre-treatment plasma identifying breast cancer: A case control study.

Background: Diabetes (primarily type 2) is linked to a higher risk of breast cancer. Insulin-like growth factor (IGF) is one of the most important factors that affects mitosis and thus inhibits apoptosis. The purpose of this study was to compare the pre-treatment insulin-like growth factor (IGF) levels in breast cancer against normal population. Methods: In this case-control study, 60 patients with breast cancer and 60 healthy controls were enrolled in 2017 and 2018 at Tehran's Shahid-Modarres Hospital. In this study, the blood sugar of the patients was examined before entering the study, and the age of the patients was also within the age limit of 18 to 70 years. They were studied to determine the relationship between insulin-like growth factor (ELISA method) and breast cancer. Results: Both groups have similar IGF-1 levels (Ctrl and Case) (P= 0.188). But, IGF-2 levels were significantly higher in breast cancer patients (373.4 vs. 317.3 ng/ml), (P=0.0001). Conclusion: According to our study, IGF-2 may serve as a prognostic biomarker and potential therapeutic target for breast cancer. However, further investigation is needed to validate this claim.

Prolactin deficiency in the context of other pituitary hormone abnormalities : Special issue: hypoprolactinemia: a neglected endocrine disorder.

Prolactin deficiency is rare. It generally occurs when pituitary disorders, such as large pituitary tumors, pituitary apoplexy, and other conditions associated with sellar mass effect lead to global failure of pituitary function and hypopituitarism. In these situiations, prolactin is commonly the last pituitary hormone affected, after growth hormone and gonadotropins are lost and thyroid-stimulating hormone and adrenocorticotopic hormone secretion is impaired. Prolactin deficiency accompanies several congenital syndromes due to mutations in PROP1 and Pit1/ POU1F and in X-linked IGSF1 deficiency syndrome, and several aqcuired conditions including Sheehan syndrome, IgG4-related hypophysitis, and immune checkpoint-inhibitor-induced hypophysitis. In women, prolactin deficiency prevents lactation following childbirth among other symptoms associated with hypopituitarism. Human prolactin is not available commercially as replacement therapy. However, recombinant human prolactin administered daily to women with hypoprolactinemia and alactogenesis was found to lead to the production of significant milk volume sufficient for lactation.

Maternal-fetal interfaces transcriptome changes associated with placental insufficiency and a novel gene therapy intervention.

The etiology of fetal growth restriction (FGR) is multifactorial, although many cases involve placental insufficiency. Placental insufficiency is associated with inadequate trophoblast invasion resulting in high resistance to blood flow, decreased availability of nutrients, and increased hypoxia. We have developed a non-viral, polymer-based nanoparticle that facilitates delivery and transient gene expression of human insulin-like 1 growth factor (hIGF1) in trophoblast for the treatment of placenta insufficiency and FGR. Using the established guinea pig maternal nutrient restriction (MNR) model of placental insufficiency, the aim of the study was to identify novel pathways in the sub-placenta/decidua that provide insight into the underlying mechanism driving placental insufficiency, and may be corrected with hIGF1 nanoparticle treatment. Pregnant guinea pigs underwent ultrasound-guided sham or hIGF1 nanoparticle treatment at mid-pregnancy, and sub-placenta/decidua tissue was collected 5 days later. Transcriptome analysis was performed using RNA Sequencing on the Illumina platform. The MNR sub-placenta/decidua demonstrated fewer maternal spiral arteries lined by trophoblast, shallower trophoblast invasion and downregulation of genelists involved in the regulation of cell migration. hIGF1 nanoparticle treatment resulted in marked changes to transporter activity in the MNR + hIGF1 sub-placenta/decidua when compared to sham MNR. Under normal growth conditions however, hIGF1 nanoparticle treatment decreased genelists enriched for kinase signaling pathways and increased genelists enriched for proteolysis indicative of homeostasis. Overall, this study identified changes to the sub-placenta/decidua transcriptome that likely result in inadequate trophoblast invasion and increases our understanding of pathways that hIGF1 nanoparticle treatment acts on in order to restore or maintain appropriate placenta function.

Unveiling the role of IGF1R in autism spectrum disorder: a multi-omics approach to decipher common pathogenic mechanisms in the IGF signaling pathway.

Autism spectrum disorder (ASD) is a complex neurodevelopmental condition marked by impairments in social interaction, communication, and repetitive behaviors. Emerging evidence suggests that the insulin-like growth factor (IGF) signaling pathway plays a critical role in ASD pathogenesis; however, the precise pathogenic mechanisms remain elusive. This study utilizes multi-omics approaches to investigate the pathogenic mechanisms of ASD susceptibility genes within the IGF pathway. Whole-exome sequencing (WES) revealed a significant enrichment of rare variants in key IGF signaling components, particularly the IGF receptor 1 (IGF1R), in a cohort of Chinese Han individuals diagnosed with ASD, as well as in ASD patients from the SFARI SPARK WES database. Subsequent single-cell RNA sequencing (scRNA-seq) of cortical tissues from children with ASD demonstrated elevated expression of IGF receptors in parvalbumin (PV) interneurons, suggesting a substantial impact on their development. Notably, IGF1R appears to mediate the effects of IGF2R on these neurons. Additionally, transcriptomic analysis of brain organoids derived from ASD patients indicated a significant association between IGF1R and ASD. Protein-protein interaction (PPI) and gene regulatory network (GRN) analyses further identified ASD susceptibility genes that interact with and regulate IGF1R expression. In conclusion, IGF1R emerges as a central node within the IGF signaling pathway, representing a potential common pathogenic mechanism and therapeutic target for ASD. These findings highlight the need for further investigation into the modulation of this pathway as a strategy for ASD intervention.

Kinase library screening identifies IGF-1R as an oncogenic vulnerability in intrahepatic cholangiocarcinoma stem-like cells.

BACKGROUND: Intrahepatic cholangiocarcinoma (iCCA) is a highly aggressive cancer of the peripheral bile ducts and is recognized by the abundance of cancer stem-like cells (CSCs) within the tumor mass. While CSC markers in iCCA are well-defined, the molecular vulnerabilities of this subpopulation remain elusive. METHODS: The 96-well, three dimensional (3D) tumorsphere culture was adapted from a well-established CSC model, validated for CSC markers through gene expression analysis. Kinase library screening was then conducted to reveal potential oncogenic vulnerable pathways. RNA interference was utilized to stably silence the candidate gene in three iCCA cell lines and its impact on iCCA cell proliferation and tumorsphere formation efficiency (TFE) was evaluated. RESULTS: Kinase inhibitor library screening identified the top 50 kinase inhibitors crucial for tumorsphere viability, with 11 inhibitors targeting the IGF-1R/PI3K/AKT axis. Further dose-dependent analysis of the top 'hit' inhibitors confirmed IGF-1R as the candidate molecule. Upon stably silencing of IGF-1R, all three iCCA cell lines exhibited decreased AKT activation, impeded proliferation and reduced TFE, indicating a decline in CSC subpopulations. CONCLUSIONS: IGF-1R plays a critical role in maintaining iCCA-stem like cell populations. GENERAL SIGNIFICANCE: Our data highlight the potential utility of IGF-1R as a prognostic marker of iCCA and a therapeutic target for eliminating its CSC subpopulation.

Genome-wide association study for growth traits with 1066 individuals in largemouth bass (Micropterus salmoides).

The largemouth bass is a native species of North America that was first introduced to mainland China in the 1980s. In recent years, it has been extensively farmed in China due to its high meat quality and broad adaptability. In this study, we collected growth trait data from 1,066 largemouth bass individuals across two populations. We generated an average of approximately 7× sequencing coverage for these fish using Illumina sequencers. From the samples, we identified 2,695,687 SNPs and retained 1,809,116 SNPs for further analysis after filtering. To estimate the number of genome-wide effective SNPs, we performed LD pruning with PLINK software and identified 77,935 SNPs. Our GWAS revealed 15 SNPs associated with six growth traits. We identified a total of 24 genes related to growth, with three genes-igf1, myf5, and myf6-directly associated with skeletal muscle development and growth, located near the leading SNP on chromosome 23. Other candidate genes are involved in the development of tissues and organs or other physiological processes. These findings provide a valuable set of SNPs and genes that could be useful for genetic breeding programs aimed at enhancing growth in largemouth bass.

Causal relationship between gut microbiota and insulin-like growth factor 1: a bidirectional two-sample Mendelian randomization study.

Background: The causal relationship between gut microbiota and insulin-like growth factor 1 (IGF-1) remains unclear. The purpose of this study was to explore the causal relationship between gut microbiota and IGF-1 in men and women. Methods: Single-nucleotide polymorphisms (SNPs) related to gut microbiota were derived from pooled statistics from large genome-wide association studies (GWASs) published by the MiBioGen consortium. Pooled data for IGF-1 were obtained from a large published GWAS. We conducted Mendelian randomization (MR) analysis, primarily using the inverse variance weighted (IVW) method. Additionally, we performed sensitivity analyses to enhance the robustness of our results, focusing on assessing heterogeneity and pleiotropy. Results: In forward MR analysis, 11 bacterial taxa were found to have a causal effect on IGF-1 in men; 14 bacterial taxa were found to have a causal effect on IGF-1 in women (IVW, all P < 0.05). After false discovery rate (FDR) correction, all bacterial traits failed to pass the FDR correction. In reverse MR analysis, IGF-1 had a causal effect on nine bacterial taxa in men and two bacterial taxa in women respectively (IVW, all P < 0.05). After FDR correction, the causal effect of IGF-1 on order Actinomycetales (PFDR = 0.049) remains in men. The robustness of the IVW results was further confirmed after heterogeneity and pleiotropy analysis. Conclusion: Our study demonstrates a bidirectional causal link between the gut microbiota and IGF-1, in both men and women.

Nanoparticle-mediated delivery of placental gene therapy via uterine artery catheterization in a pregnant rhesus macaque.

Nanoparticles offer promise as a mechanism to non-invasively deliver targeted placental therapeutics. Our previous studies utilizing intraplacental administration demonstrate efficient nanoparticle uptake into placental trophoblast cells and overexpression of human IGF1 (hIGF1). Nanoparticle-mediated placental overexpression of hIGF1 in small animal models of placental insufficiency and fetal growth restriction improved nutrient transport and restored fetal growth. The objective of this pilot study was to extend these studies to the pregnant nonhuman primate and develop a method for local delivery of nanoparticles to the placenta via maternal blood flow from the uterine artery. Nanoparticles containing hIGF1 plasmid driven by the placenta-specific PLAC1 promoter were delivered to a mid-gestation pregnant rhesus macaque via a catheterization approach that is clinically used for uterine artery embolization. Maternal-fetal interface, fetal and maternal tissues were collected four days post-treatment to evaluate the efficacy of hIGF1 treatment in the placenta. The uterine artery catheterization procedure and nanoparticle treatment was well tolerated by the dam and fetus through the four-day study period following catheterization. Nanoparticles were taken up by the placenta from maternal blood as plasmid-specific hIGF1 expression was detected in multiple regions of the placenta via in situ hybridization and qPCR. The uterine artery catheterization approach enabled successful delivery of nanoparticles to maternal circulation in close proximity to the placenta with no concerns to maternal or fetal health in this short-term feasibility study. In the future, this delivery approach can be used for preclinical evaluation of the long-term safety and efficacy of nanoparticle-mediated placental therapies in a rhesus macaque model.

Placental Gene Therapy for Fetal Growth Restriction and Preeclampsia: Preclinical Studies and Prospects for Clinical Application.

In the last three decades, gene therapy has demonstrated significant progress. Over 700 active investigational new drug (IND) applications have been reported. Research on in utero gene therapy has advanced, but ethical and safety concerns persist. A novel approach under investigation is placental gene therapy, which holds promise for targeting diseases associated with placental dysfunction, such as fetal growth restriction (FGR) and preeclampsia. One of the underlying causes of placental insufficiency in these conditions is reduced placental growth factor-driven angiogenesis and endothelial cell dysfunction during fetal development. Studies have explored the overexpression of growth factor transgenes like IGF-1 to address FGR, yielding promising outcomes in animal models. Furthermore, intra-placental gene transfer, instead of systemic delivery of gene therapy vectors, has the potential to treat and cure these disorders. However, challenges and limitations akin to in utero gene therapy persist, including the risk of in utero infection, potential impairment of the mother's future fertility, the risk of germline integration, and possible off-target effects of gene transfer in the fetus or the mother. Consequently, additional research and deliberation within the scientific and medical communities are warranted to fully comprehend the potential benefits and risks of placental gene therapy.

A genetic investigation in five Chinese families with keratoconus.

Background: This study investigated the genetic characteristics of five Chinese families with keratoconus (KC). Methods: In the five families affected by KC, medical records, clinical observations, and blood samples were collected from all individuals. All KC family members (n = 20) underwent both whole exome sequencing of genomic DNA and Sanger sequencing to confirm the variants. Online software was utilized to analyze all variants, and the online server I-TASSER was employed for in silico predictions of the three-dimensional protein structures of the variants. The newly discovered variants and single nucleotide polymorphisms were further examined in 322 sporadic KC patients. Results: The Pentacam tomographic composite index in those affected first-degree family members of the probands showed a pathological change. Five new variants were detected in the five probands and other affected members in their families: a heterozygous missense variant g.19043832C>T (p.Ser145Asn) in the homer scaffolding protein 3 (HOMER3) gene; a heterozygous missense variant g.99452113G>A (p.Gly483Arg) in the insulin-like growth factor 1 receptor (IGF1R) gene; a heterozygous missense variant g.55118280G>T (p.Trp843Leu) in the echinoderm microtubule-associated protein like 6 (EML6) gene; a heterozygous frameshift variant c. 1226_1227del (p.Gln410Glufs*17) in the DOP1 leucine zipper-like protein B (DOP1B) gene; and a heterozygous splice-site variant c.7776+2T>A in the neurobeachin-like protein 2 (NBEAL2) gene. These variations were predicted to be potentially pathogenic and associated with KC. Conclusion: Five novel variants in HOMER3, IGF1R, EML6, DOP1B, and NBEAL2 genes were identified in this study and may be associated with the pathogenesis of KC. This study provides new information about the gene variants and their protein changes in KC patients. The findings should be explored further and could potentially be applied to the early diagnosis of KC before clinical onset.

Slow growth and short stature in children with attention deficit hyperactivity disorder (ADHD): a retrospective study of 493 children who underwent growth hormone provocation testing at one tertiary paediatric endocrine centre.

OBJECTIVES: We hypothesised that growth hormone (GH) deficiency (GHD) in children with attention deficit hyperactivity disorder (ADHD) is rare. This study aimed to determine any distinct clinical or biochemical parameters, including GH provocation testing, in children with ADHD on psychostimulants or idiopathic short stature (ISS). METHODS: Retrospective cross-sectional study of children who had GH provocative testing between 1998 and 2013 at one tertiary paediatric endocrine centre. Clinical data included age, sex, anthropometry, pubertal staging, bone age, diagnostic code as per the European Society Paediatric Endocrinology (ESPE), GH provocation test results, thyroid function tests, serum insulin-like growth factor-1 (IGF-1) and insulin-like growth factor-binding protein-3 (IGFBP-3) levels. RESULTS: Four hundred ninety-three subjects underwent GH provocation testing for investigation of short stature to exclude GHD during the study period. Fifty-one children had a diagnosis of ADHD. In the remaining children, the diagnosis was Idiopathic short stature (n=240), GHD +/- hypopituitarism (n=60), and 142 subjects had other causes of short stature. Children with ADHD were older, had higher height and weight SDS and were GH-sufficient. All 51 children with ADHD had a normal serum IGFBP-3, while 20 out of these 51 subjects had a low serum IGF-1. CONCLUSIONS: GHD in children with ADHD on psychostimulant medication is rare. GH testing in children with ADHD may not be necessary, particularly if serum IGFBP-3 is in the normal range. We suggest IGFBP-3 could be used as a surrogate marker of GH sufficiency in children with ADHD. However, this needs to be confirmed with a larger study group.

Bayesian Individual Limits for IGF-1 Monitoring in Equine Plasma: Implementation in the Equine Biological Passport.

Despite the International Federation of Horseracing Authorities (IFHA) regulation associated with heavy sanctions, the abuse of prohibited substances must be identified and deterred throughout horses' athletic careers, such as the administration of recombinant growth hormone (rGH). GH is naturally produced in mammal organisms to stimulate growth. Thus, rGH administration can enhance the performance of horses by expanding some physical abilities. As measuring endogenous GH levels is complex, an indirect strategy is to monitor GH-associated biomarkers in plasma as insulin-like growth factor 1 (IGF-1) levels. To prevent these misuses, the Equine Biological Passport (EBP) has been designed in France (GIE LCH) and Australia (ARFL-Racing NSW) to profile specific biological and chemical parameters in selected racehorses. In this study, we investigated individual limits as a complementary tool to a single limit to supervise the stability of IGF-1 profile over a racing season. The aim is to design custom limits based on the horse's history to detect any deviation below the single limit. The method was assessed using experimental data and then tested on EBP data from three thoroughbreds and three French trotters. Finally, individual limits have been added to the French EBP for IGF-1 monitoring.

The pro-atherogenic enzyme PAPP-A is active in eluates from human carotid and femoral atherosclerotic plaques.

Background: Pregnancy-associated plasma protein-A (PAPP-A) regulates bioavailability of insulin-like growth factor 1 (IGF1) in various tissues by proteolytic cleavage of a subset of IGF-binding proteins (IGFBPs). Pre-clinical studies have established a role of PAPP-A in atherosclerosis and proposed that targeting the proteolytic activity of PAPP-A has therapeutic value.This study aimed to investigate whether human atherosclerotic plaques contain proteolytically active PAPP-A, a prerequisite for further considering PAPP-A as a therapeutic target in patients. Methods: We obtained carotid (n = 9) and femoral (n = 11) atherosclerotic plaques from patients undergoing vascular surgery and incubated freshly harvested plaque tissue in culture media for 24 h. Subsequently, conditioned media were assayed for PAPP-A, STC2, IGFBP4, and IGF1 using immunoassays. Enzymatic activity of PAPP-A was assessed by its ability to process recombinant IGFBP4-IGF1 complexes - a specific substrate of PAPP-A - by Western blotting. Results: PAPP-A and STC2 were detectable in conditioned media from both carotid and femoral plaques, with higher STC2 concentrations in eluates from carotid plaque incubations (p = 0.02). IGFBP4 and IGF1 were undetectable. Conditioned media from all 20 plaques exhibited PAPP-A proteolytic activity. However, no correlation between PAPP-A concentration and its proteolytic activity was observed, whereas the PAPP-A: STC2 molar ratio correlated with PAPP-A activity (R2 = 0.25, p = 0.03). Conclusion: This study provides evidence for the presence of enzymatically active PAPP-A in atherosclerotic plaques and underscores the need for further investigating potential beneficial effects associated with targeting PAPP-A in atherosclerotic cardiovascular disease.

Message Transmission Between Adipocyte and Macrophage in Obesity.

Obesity is characterized by the chronic low-grade activation of the innate immune system. In this respect, macrophage-elicited metabolic inflammation and adipocyte-macrophage interaction have primary importance in obesity. Large quantity of macrophages is accumulated by different mechanisms in obese adipose tissue. Hypertrophic adipocyte-derived chemotactic monocyte chemoattractant protein-1 (MCP-1)/C-C chemokine receptor 2 (CCR2) pathway promotes more macrophage accumulation into the obese adipose tissue. However, obesity-induced changes in adipose tissue macrophage density are mainly dependent on increases in the triple-positive cluster of differentiation (CD)11b+ F4/80+ CD11c+ adipose tissue macrophage subpopulation. As epigenetic regulators, microRNAs (miRNAs) are one of the most important mediators of obesity. miRNAs are expressed by adipocytes as well as macrophages and regulate inflammation with the expression of target genes. A paracrine loop involving free fatty acids and tumor necrosis factor-alpha (TNF-α) between adipocytes and macrophages establishes a vicious cycle that aggravates inflammatory changes in the adipose tissue. Adipocyte-specific caspase-1 and production of interleukin-1beta (IL-1ß) by macrophages; both adipocyte and macrophage induction by toll-like receptor-4 (TLR4) through nuclear factor-kappaB (NF-κB) activation; free fatty acid-induced and TLR-mediated activation of c-Jun N-terminal kinase (JNK)-related pro-inflammatory pathways in CD11c+ immune cells; are effective in mutual message transmission between adipocyte and macrophage and in the development of adipose tissue inflammation. Thus, the metabolic status of adipocytes and their released exosomes are important determinants of macrophage inflammatory output. However, old adipocytes are removed by macrophages through trogocytosis or sending an "eat me" signal. As a single miRNA can be able to regulate a variety of target genes and signaling pathways, reciprocal transfer of miRNAs between adipocytes and macrophages via miRNA-loaded exosomes reorganizes the different stages of obesity. Changes in the expression of circulating miRNAs because of obesity progression or anti-obesity treatment indicate that miRNAs could be used as potential biomarkers. Therefore, it is believed that targeting macrophage-associated miRNAs with anti-obesity miRNA-loaded nano-carriers may be successful in the attenuation of both obesity and adipose tissue inflammation in clinical practice. Moreover, miRNA-containing exosomes and transferable mitochondria between the adipocyte and macrophage are investigated as new therapeutic targets for obesity-related metabolic disorders.

IGF 1, BDNF, and NGF mediate the neuro-modulatory role of stem cells in acrylamide-induced hippocampal toxic changes in rats.

BACKGROUND: Acrylamide (ACR), a common industrial chemical, is a strong neurotoxic material. The hippocampus is a brain area of interest mostly affected by Alzheimer's disease. Mesenchymal stem cells (MSCs) usefulness in various neurological diseases including Alzheimer's is being debated. In this work, the authors aim to explore the role of MSCs in ACR-induced hippocampal neurodegeneration and elucidate the mediating mechanism. MATERIALS AND METHODS: For this purpose, ten rats served as control, another ten were injected ACR (i.p. 50 mg/kg/day for 2 weeks), and the last ten rats were injected ACR in addition to MSCs (i.p. 1 × 107 MSCs single injection). RESULTS: ACR induced neurodegenerative histopathological hippocampal changes and adversely altered hippocampal oxidative stress markers SOD, MDA, and GSH. ACR had induced hippocampal demyelination as detected by silver staining. ACR significantly (P < 0.05) up-regulated the ELISA hippocampal TNF-alpha and IL-6 and produced microglial & astrocyte activation (as tracked by Iba1 & GFAP immunohistochemistry respectively). ACR significantly reduced hippocampal PCR gene expression of IGF 1 (insulin growth factor-1), BDNF (brain-derived neurotrophic factor), and NGF (nerve growth factor). MSCs administration had mitigated all the previous deleterious changes. CONCLUSIONS: Acrylamide caused detrimental effects on the hippocampus and demonstrably altered the hippocampal architecture. Bone marrow mesenchymal stem cells offered a promising therapeutic role against these neurotoxic effects of acrylamide, presumably through modulation of IGF 1, BDNF, and NGF gene expressions.

Fluorescent tagging of endogenous IRS2 with an auxin-dependent degron to assess dynamic intracellular localization and function.

Insulin Receptor Substrate 2 (IRS2) is a signaling adaptor protein for the insulin (IR) and Insulin-like Growth Factor-1 (IGF-1R) receptors. In breast cancer, IRS2 contributes to both initiation of primary tumor growth and establishment of secondary metastases through regulation of cancer stem cell (CSC) function and invasion. However, how IRS2 mediates its diverse functions is not well understood. We used CRISPR/Cas9-mediated gene editing to modify endogenous IRS2 to study the expression, localization, and function of this adaptor protein. A cassette containing an auxin inducible degradation (AID) sequence, 3X-FLAG tag and mNeon-green was introduced at the N-terminus of the IRS2 gene to provide rapid and reversible control of IRS2 protein degradation and analysis of endogenous IRS2 expression and localization. Live fluorescence imaging of these cells revealed that IRS2 shuttles between the cytoplasm and nucleus in response to growth regulatory signals in a PI3K-dependent manner. Inhibition of nuclear export or deletion of a putative nuclear export sequence in the C-terminal tail promotes nuclear retention of IRS2, implicating nuclear export in the mechanism by which IRS2 intracellular localization is regulated. Moreover, the acute induction of IRS2 degradation reduces tumor cell invasion, demonstrating the potential for therapeutic targeting of this adaptor protein. Our data highlight the value of our model of endogenously tagged IRS2 as a tool to study IRS2 localization and function.

Effect of Extracorporeal Shock Wave on IGF-1, TNF-α, and IL-1in Joint Fluid of Patients with Temporomandibular Joint Disorder Syndrome.

As a new therapeutic method, extracorporeal shock wave (ESW) has shown remarkable efficacy in the treatment of temporomandibular joint disorder syndrome. Numerous studies have shown that it has the advantages of noninvasiveness, short treatment time, etc. It can effectively relieve pain and improve symptoms such as joint mobility and opening degree. In clinical practice, through accurate diagnosis and positioning of different patients, appropriate treatment parameters such as therapeutic transducer, frequency and pressure can be selected to significantly improve the efficacy. At the same time, follow-up evaluation after treatment, including temporomandibular joint disorder index and visual analogue score, is also helpful to fully understand the rehabilitation of patients. Extracorporeal shock wave therapy (ESWT) brings new hope to patients with temporomandibular joint disorder syndrome and has a broad application prospect.

Changes in hormonal profiles during competition preparation in physique athletes.

PURPOSE: Physique athletes engage in rigorous competition preparation involving intense energy restriction and physical training to enhance muscle definition. This study investigates hormonal changes and their physiological and performance impacts during such preparation. METHODS: Participants included female (10 competing (COMP) and 10 non-dieting controls (CTRL)) and male (13 COMP and 10 CTRL) physique athletes. COMP participants were tested 23 weeks before (PRE), one week before (MID), and 23 weeks after the competition (POST). Non-dieting CTRL participants were tested at similar intervals. Measurements included body composition (DXA), muscle cross-sectional area (ultrasound), energy availability (EA) derived by subtracting exercise energy expenditure (EEE) from energy intake (EI) and dividing by fat-free mass (FFM), muscle strength, and various serum hormone concentrations (ACTH, cortisol, estradiol, FSH, IGF-1, IGFBP-3, insulin, and free and total testosterone and SHBG). RESULTS: During the diet, EA (p < 0.001), IGF-1 (p < 0.001), IGFBP-3 (p < 0.01), and absolute muscle strength (p < 0.01-0.001) decreased significantly in both sexes in COMP. Decreases in IGF-1 were also associated with higher loss in FFM. In males, testosterone (p < 0.01) and free testosterone (p < 0.05) decreased, while SHBG (p < 0.001) and cortisol (p < 0.05) increased. Insulin decreased significantly only in males (p < 0.001). Mood disturbances, particularly increased fatigue in males (p < 0.05), highlighted the psychological strain of competition preparation. All these changes were restored by increased EA during the post-competition recovery period. CONCLUSION: Significant reductions in IGF-1 and IGFBP-3 during competition preparation may serve as biomarkers for monitoring physiological stress. This study offers valuable insights into hormonal changes, muscle strength, and mood state during energy-restricted intense training.