Inhibition of circular JUN prevents the proliferation and invasion of glioblastoma via miR-3064-IGFBP5 axis.

Glioblastoma (GBM) remains one of the most aggressive and lethal brain tumours, characterized by rapid progression and limited treatment options. This study investigated the regulatory roles of circular RNA circJUN, and its functional interaction with microRNA miR-3064 in GBM pathogenesis. We employed bioinformatic analyses and clinical sample validation to identify circJUN as a potential target in GBM. Subsequently, we engineered GBM cell lines with stable circJUN knockout or overexpression, and transfected them with miR-3064 mimic/inhibitor or IGFBP5 small interfering RNA (siRNA)/expression vector to elucidate the molecular mechanisms governing GBM proliferation and invasion. To investigate the in vivo effects, xenograft tumour models were established in nude mice using engineered cells to assess the roles of circJUN in tumour growth regulation. Our analyses revealed significant overexpression of circJUN in GBM tissues compared to healthy controls, which strongly correlated with poor patient prognosis. In vitro and in vivo experiments demonstrated that circJUN overexpression could enhance GBM cell proliferation and invasion. Mechanistic investigations uncovered EIF4A3 as an interacting factor of circJUN which promotes circJUN expression, and circJUN modulates miR-3064 activity to regulate the malignancy of GBM cells. Furthermore, we identified IGFBP5, a crucial regulator of cell growth, as a direct target of miR-3064, thereby establishing an additional layer of control over GBM proliferation and invasion. Our study unveils a complex regulatory network involving circJUN, miR-3064 and IGFBP5 in GBM pathogenesis, underscoring their potential as novel therapeutic targets for improving patient outcomes. Our findings not only contribute to the understanding of GBM biology but also pave the way for innovative therapeutic approaches in the management of this malignancy.

METTL3 inhibitor suppresses the progression of prostate cancer via IGFBP3/AKT pathway and synergizes with PARP inhibitor.

The RNA N6-methyladenosine (m6A) regulator METTL3 is an important regulatory gene in various progressive processes of prostate cancer (PCa). METTL3 inhibitors have been reported to possess potent tumor suppression capacity in some cancer types. Nevertheless, the detailed influence and mechanism of METTL3 inhibitors on PCa progression and their potential synergy with other drugs are poorly understood. In this study, we demonstrated that METTL3 was overexpressed and associated with poor survival in most PCa patients. METTL3 inhibitor STM2457 reduced m6A levels of PCa cells, thus inhibiting their proliferation, colony formation, migration, invasion, and stemness in vitro. Furthermore, STM2457 suppressed PCa progression in both the CDX and PDX models in vivo. MeRIP-seq analysis coupled with biological validation revealed that STM2457 influenced multiple biological processes in PCa cells, mainly through the IGFBP3/AKT pathway. We also proved that STM2457 induced DNA damage and showed synergistic anti-PCa effects with the PARP inhibitor olaparib both in vitro and in vivo. All in all, this work provides a novel therapeutic strategy for targeting RNA m6A modifications for the treatment of PCa and provides a meaningful reference for further clinical trials.

Deciphering the multidimensional impact of IGFBP1 expression on cancer prognosis, genetic alterations, and cellular functionality: A comprehensive Pan-cancer analysis.

Objectives: IGF-binding protein 1 (IGFBP1) is a key regulator of insulin-like growth factors, impacting biological processes, including cancer progression and prognosis. Materials and methods: This study investigates genetic alterations affecting IGFBP1 expression in tumors using data from The Cancer Genome Atlas (TCGA) PanCancer Atlas via cBioPortal. We analyzed samples from 32 cancer types for mutation sites, including deep deletions, amplifications, and mutations. RNA-seq data were normalized using log2(value + 1). Statistical analyses, including survival outcomes, were conducted using R packages like ggplot2, stats, and car. Kaplan-Meier survival curves and log-rank tests assessed overall survival (OS) and progression-free survival (PFS). Univariate Cox regression was used to develop nomogram models for OS. Functional consequences of IGFBP1 mutations were explored through protein structure, stability, and IGF interaction analyses. Protein-protein interaction networks and functional enrichment were analyzed using GEPIA2, STRING, and Cytoscape. Gene Ontology (GO), KEGG, and Gene Set Enrichment Analysis (GSEA) provided insights into affected biological pathways. Results: Pan-cancer analysis revealed diverse expression patterns, including significant upregulation in cutaneous melanoma (SKCM) and downregulation in lung adenocarcinoma (LUAD) and stomach adenocarcinoma (STAD). Specifically, elevated IGFBP1 expression in SKCM patients led to a 25 % improvement in 5-year survival. In contrast, higher IGFBP1 levels in LUAD and OV patients resulted in a 30 % and 20 % decrease in survival, respectively. Elevated IGFBP1 levels are significantly linked to advanced tumor stage and grade in OV and LUAD, affecting prognostic outcomes. Nomogram models for OV, SKCM, LUAD, and STAD showed IGFBP1's predictive strength with AUC values ranging from 0.70 to 0.85, indicating its diagnostic potential. Genetic analyses revealed mutations in IGFBP1 in 12 % of STAD cases and 10 % of UCEC cases, indicating significant genetic variation. Immune analysis showed that high IGFBP1 expression significantly influenced immune cell infiltration, particularly macrophages and CD8+ T cells, thereby affecting survival in LUAD and OV. Functional enrichment and gene set enrichment analysis identified IGFBP1 involvement in crucial pathways, such as cell cycle regulation, immune response, and PD-1 signaling, highlighting its biological impact. Additionally, IGFBP1 expression delineates distinct molecular and immune subtypes, correlating with specific cancer behaviors and immune patterns. Conclusions: These findings highlight IGFBP1's potential as a biomarker and therapeutic target, particularly for immunoregulation and cancer subtype stratification.

The 5:2 Diet Affects Markers of Insulin Secretion and Sensitivity in Subjects with and without Type 2 Diabetes-A Non-Randomized Controlled Trial.

This non-randomized controlled trial aimed to compare the effect of the 5:2 diet on insulin levels as a primary outcome and markers of insulin secretion (connecting peptide (C-peptide) and insulin-like growth factor binding protein-1 (IGFBP-1)) and sensitivity (Homeostatic Model Assessment for Insulin Resistance (HOMA-IR)), as well as body composition as secondary outcomes in overweight/obese individuals with and without type 2 diabetes (T2D). Ninety-seven participants (62% women), 35 with T2D and 62 BMI- and waist-matched controls without T2D, followed the 5:2 diet (two days per week of fasting) for six months with a 12-month follow-up. At six months, there was no loss to follow-up in the T2D group, whereas four controls discontinued this study. Overall, 82% attended the 12-month follow-up. After the intervention, insulin levels decreased in the control group and glucose decreased in the T2D group, while C-peptide, HOMA-IR, waist circumference, BMI, trunk, and total fat% decreased in both groups. Furthermore, low IGFBP-1, indicating hyperinsulinemia, improved in the T2D group. The changes in fasting glucose and waist measurement were significantly more improved in the T2D group than in the controls. Persistent positive effects were observed at the 12-month follow-up. The 5:2 diet for six months was feasible and efficient to reduce markers of insulin secretion and resistance and therefore holds promise as management of overweight/obesity in subjects with and without T2D.

Insulin-like growth factor-binding protein7 exacerbates inflammatory response and lipid metabolism imbalance in alcohol-associated liver disease.

Alcohol-associated liver disease(ALD), caused by excessive alcohol consumption, are often associated with inflammatory outbreaks and lipid deposition in the liver. The role of Insulin-like growth factor-binding protein 7 (IGFBP7), an important metabolic regulator, in ALD, its underlying regulatory mechanism, and its potential implication in anti-ALD therapies remain unknown. We investigated the effects of IGFBP7 on hepatic inflammation and lipid metabolism disruption in a mouse model of ALD. Mice were fed by chronic ethanol feeding plus a single binge of ethanol feeding(chronic-plus-single-binge model). In addition, ethanol exposure modeling studies were performed on cultured hepatocytes to verify molecular correlations. The results showed that IGFBP7 expression was significantly elevated in the livers of mice and hepatocytes after chronic ethanol exposure. Subsequently, the results of a study by specific knockout of IGFBP7(IGFBP7-cKO) in mouse hepatocytes and lentiviral silencing of IGFBP7 in vivo suggested that IGFBP7 deletion could improve liver function levels in alcohol-fed mice; It also attenuated the outbreak of hepatitis factor and the disorder of lipid metabolism in mice.Using RNA-seq sequencing of mouse liver tissue, we found that IGFBP7 affects several downstream metabolic signaling pathways, including PPAR, MAPK, FoxO, etc. Then, we used the PPARα plasmid in hepatocytes and discovered that overexpressing PPARα reversed the impact of IGFBP7 on lipid metabolism disorders in hepatocytes. In conclusion, IGFBP7 deficiency in alcohol-associated liver disease alleviates the decline in liver function and the imbalance of lipid metabolism in mice, attenuates the inflammatory outbreak, and affects a variety of downstream lipid metabolism factors by regulating PPARα. Hence, IGFBP7 may be an effective therapeutic target in the treatment of ALD.

Prediction of gestational diabetes mellitus by multiple biomarkers at early gestation.

BACKGROUND: It remains unclear which early gestational biomarkers can be used in predicting later development of gestational diabetes mellitus (GDM). We sought to identify the optimal combination of early gestational biomarkers in predicting GDM in machine learning (ML) models. METHODS: This was a nested case-control study including 100 pairs of GDM and euglycemic (control) pregnancies in the Early Life Plan cohort in Shanghai, China. High sensitivity C reactive protein, sex hormone binding globulin, insulin-like growth factor I, IGF binding protein 2 (IGFBP-2), total and high molecular weight adiponectin and glycosylated fibronectin concentrations were measured in serum samples at 11-14 weeks of gestation. Routine first-trimester blood test biomarkers included fasting plasma glucose (FPG), serum lipids and thyroid hormones. Five ML models [stepwise logistic regression, least absolute shrinkage and selection operator (LASSO), random forest, support vector machine and k-nearest neighbor] were employed to predict GDM. The study subjects were randomly split into two sets for model development (training set, n = 70 GDM/control pairs) and validation (testing set: n = 30 GDM/control pairs). Model performance was evaluated by the area under the curve (AUC) in receiver operating characteristics. RESULTS: FPG and IGFBP-2 were consistently selected as predictors of GDM in all ML models. The random forest model including FPG and IGFBP-2 performed the best (AUC 0.80, accuracy 0.72, sensitivity 0.87, specificity 0.57). Adding more predictors did not improve the discriminant power. CONCLUSION: The combination of FPG and IGFBP-2 at early gestation (11-14 weeks) could predict later development of GDM with moderate discriminant power. Further validation studies are warranted to assess the utility of this simple combination model in other independent cohorts.

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.

IGFBP7 promotes the proliferation and differentiation of primary myoblasts and intramuscular preadipocytes in chicken.

Though it is well known that insulin-like growth factor (IGF) binding protein 7 (IGFBP7) plays an important role in myogenesis and adipogenesis in mammals, its impact on the proliferation, differentiation, and lipid deposition in chicken primary myoblasts (CPM) and intramuscular preadipocytes remains unexplored. In the present study, we firstly examined the correlation between SNPs within the genomic sequence of the IGFBP7 gene and carcass and blood chemical traits in a F2 resource population by genetic association analysis, and found that a significant correlation between the SNP (4_49499525) located in the intron region of IGFBP7 and serum high-density lipoproteins (HDL). We then examined the expression patterns of IGFBP7 across different stages of proliferation and differentiation in CPMs and intramuscular preadipocytes via qPCR, and explored the biological functions of IGFBP7 through gain- and loss-of-function experiments and a range of techniques including qPCR, CCK-8, EdU, flow cytometry, Western blot, immunofluorescence, and Oil Red O staining to detect the proliferation, differentiation, and lipid deposition in CPMs and intramuscular preadipocytes. We ascertained that the expression levels of the IGFBP7 gene increased as cell differentiation progresses in CPMs and intramuscular preadipocytes, and that IGFBP7 promotes the proliferation and differentiation of these cells, as well as facilitates intracellular lipid deposition. Furthermore, we investigated the regulatory mechanism of IGFBP7 expression by using co-transfection strategy and dual-luciferase reporter assay, and discovered that the myogenic transcription factors (MRF), myoblast determination factor (MyoD) and myogenin (MyoG), along with the adipocyte-specific transcription factor (TF) CCAAT/enhancer-binding protein α (C/EBPα), can bind to the core transcription activation region of the IGFBP7 promoter located 500 bp upstream from the transcription start site, thereby promoting IGFBP7 transcription and expression. Taken together, our study underscores the role of IGFBP7 as a positive regulator for myogenesis and adipogenesis, while also elucidating the functional and transcriptional regulatory mechanisms of IGFBP7 in chicken skeletal muscle development and intramuscular adipogenesis.

Banxia Xiexin Tang attenuates high glucose-induced hepatocyte injury by activating SOD2 to scavenge ROS via PGC-1α/IGFBP1.

This study aimed to explore the protective mechanism of Banxia Xiexin Tang (BXXXT) on liver cell damage caused by high glucose (H-G) and to clarify its molecular regulatory pathways. First, the main components in BXXXT-containing serum were analyzed by high-performance liquid chromatography (HPLC) to provide basic data for subsequent experiments. Subsequently, the effect of BXXXT on high glucose (H-G)-induced hepatocyte activity was evaluated through screening of the optimal concentration of drug-containing serum. Experimental results showed that BXXXT significantly reduced the loss of cell activity caused by high glucose. Further research focuses on the regulatory effect of BXXXT on high glucose-induced hepatocyte apoptosis, especially its effect on the PGC-1α (peroxisome proliferator-activated receptor γ coactivator-1α) pathway. Experimental results showed that BXXXT reduced high-glucose-induced hepatocyte apoptosis and exerted its protective effect by upregulating the activity of the PGC-1α pathway. BXXXT significantly increased the expression level of IGFBP1 (insulin-like growth factor-binding proteins) in hepatocytes under a high-glucose environment. It cleared mitochondrial ROS (reactive oxygen species) by enhancing SOD2 (superoxide dismutase) enzyme activity and maintained the survival of hepatocytes under a high-glucose environment. Finally, the regulation of PGC-1α by BXXXT is indeed involved in the regulation of IGFBP1 expression in hepatocytes and its downstream SOD2 effector signaling. Taken together, this study provides an in-depth explanation of the protective mechanism of BXXXT on hepatocytes in a high-glucose environment, focusing on regulating the expression of the PGC-1α pathway and IGFBP1, and reducing cell damage by scavenging ROS. This provides an experimental basis for further exploring the potential of BXXXT in the treatment of diabetes-related liver injury. Supplementary Information: The online version contains supplementary material available at 10.1007/s13205-024-04060-0.

Prognostic and diagnostic value of circulating IGFBP2 in pancreatic cancer.

Insulin-like growth factor binding protein 2 (IGFBP2) is overexpressed in tumor tissues of several malignancies, including pancreatic cancer. Because of its role in tumor progression, IGFBP2 has been investigated as a tumor biomarker. However, little is known about its utility in pancreatic cancer. Plasma IGFBP2 levels were determined using enzyme-linked immunosorbent assay in 75 patients with pancreatic ductal adenocarcinoma (PDAC), 73 matched healthy controls, and 17 chronic pancreatitis patients. Our results showed that the plasma IGFPB2 level was significantly higher in PDAC patients than in patients with chronic pancreatitis and healthy controls. At a cut-off value of 333.9 ng/mL, the specificity and sensitivity were 78.08 and 65.33%, respectively. IGFBP2 level alone did not outperform carbohydrate antigen 19-9 (CA19-9) in diagnostic accuracy, but it successfully identified 9 out of 24 PDAC patients who were misidentified by CA19-9. The combination of IGFBP2 and CA19-9 was more accurate in the detection of PDAC than CA19-9 alone. IGFBP2 was more accurate than the other in discriminating between chronic pancreatitis and PDAC. Plasma IGFBP2, rather than CA19-9, was higher in the new-onset diabetes, lymph node involvement, and distant metastasis subgroups. IGFBP2 level was notably higher in stage IV cases than in stage I/II or stage III disease. However, CA19-9 did not show a difference between stages. After adjusting for lymph node involvement and distant metastasis, plasma IGFBP2 was identified as an independent prognostic marker for PDAC. The median survival time for patients with an IGFBP2 level ≥333.9 ng/mL was significantly shorter than that for patients with an IGFBP2 level <333.9 ng/mL. Marked elevation of plasma IGFBP2 in PDAC is associated with poorer survival. IGFBP2 may be considered as a supplementary biomarker for the diagnosis and prognostic prediction in Chinese pancreatic cancer patients.

Prognostic Value of IGFBP6 in Breast Cancer: Focus on Glucometabolism.

IGFBP6, a member of the IGF binding protein (IGFBP) family, is a specific inhibitor of insulin-like growth factor II (IGF-II) and can inhibit the growth of malignant tumors overexpressing IGF-II. Type 2 diabetes (T2D) is a basic disorder of glucose metabolism that can be regulated by IGF-related pathways. We performed bioinformatics analysis of the TCGA database to explore the possible mechanism of IGFBP6 in breast cancer (BC) metabolism and prognosis and collected clinical samples from BC patients with and without T2D to compare and verify the prognostic effect of IGFBP6. In our study, the levels of IGFBP1-6 were positively correlated with overall survival (OS) in patients with breast cancer. IGFBP6 was upregulated in estrogen receptor (ER)-positive BC, and ER-positive and progesterone receptor (PR) positive patients had a higher expression level of IGFBP6 than ER-negative and PR-negative patients. IGFBP6 could be used as an independent prognostic factor in BC. The expression of IGFBP6 was decreased in BC tissue, and BC tissue from patients with T2D had lower IGFBP6 expression levels than BC tissue from patients without T2D. IGFBP6 is mainly involved in the PI3K-Akt and TGF-ß signaling pathways and tumor microenvironment regulation. In terms of metabolism, the expression of IGFBP6 was negatively correlated with that of most glucose metabolism-related genes. IGFBP6 expression was mainly correlated with mutations in TP53, PIK3CA, CDH1, and MAP3K1. In addition, the upregulation of IGFBP6 in BC increased the drug sensitivity to docetaxel, paclitaxel and gemcitabine. Overall, these results indicated that high expression of IGFBP6 is associated with a good prognosis in BC patients, especially in those without T2D. It is not only involved in the maintenance of the tumor microenvironment in BC but also inhibits the energy metabolism of cancer cells through glucose metabolism-related pathways. These findings may provide a new perspective on IGFBP6 as a potential prognostic marker for BC.

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.

IGF Signaling in the Heart in Health and Disease.

One of the most vital processes of the body is the cardiovascular system's proper operation. Physiological processes in the heart are regulated by the balance of cardioprotective and pathological mechanisms. The insulin-like growth factor system (IGF system, IGF signaling pathway) plays a pivotal role in regulating growth and development of various cells and tissues. In myocardium, the IGF system provides cardioprotective effects as well as participates in pathological processes. This review summarizes recent data on the role of IGF signaling in cardioprotection and pathogenesis of various cardiovascular diseases, as well as analyzes severity of these effects in various scenarios.

[Corrigendum] The role of IGFBP­5 in mediating the anti­proliferation effect of tetrandrine in human colon cancer cells.

Following the publication of the above article, a concerned reader drew to the authors' attention that, among Figs. 1D, 2A and 4B, certain of the control western blots had been re­used in different blots. The authors have retrieved and re­examined their original data, and were able to identify the correct control western blots where the data had been inadvertently duplicated in the affected original figures. The revised versions of Figs. 2 and 4, now featuring the correct control western blots, are shown in the subsequent two pages. The authors regret that the data in question featured in the original article had been re­used, and thank the Editor of International Journal of Oncology for granting them the opportunity to publish this corrigendum. All the authors agree with the publication of this corrigendum; furthermore, they apologize to the readership of the journal for any inconvenience caused. [International Journal of Oncology 46: 1205­1213, 2015; DOI: 10.3892/ijo.2014.2800].

Discovering genes and microRNAs involved in human lung development unveils IGFBP3/miR-34a dynamics and their relevance for alveolar differentiation.

BACKGROUND: During pseudoglandular stage of the human lung development the primitive bronchial buds are initially conformed by simple tubules lined by endoderm-derived epithelium surrounded by mesenchyme, which will progressively branch into airways and start to form distal epithelial saculles. For first time alveolar type II (AT2) pneumocytes appears. This study aims to characterize the genes and microRNAs involved in this differentiation process and decipher its role in the starting alveolar differentiation. METHODS: Gene and microRNA profiling was performed in human embryonic lungs from 7 to 12 post conception weeks (pcw). Protein expression location of candidate genes were analyzed by immunofluorescense in embryonic lung tissue sections. mRNA/miRNA target pairs were identified using computational approaches and their expression was studied in purified epithelial/mesenchymal cell populations and in isolated tips and stalks from the bronchial tree. Additionally, silencing experiments in human embryonic lung mesenchymal cells and in human embryonic tip-derived lung organoids were performed, as well as organoid differentiation studies. AT2 cell markers were studied by qRT-PCR and by immunofluorescence. The TGFB-ß phosphorylated pathways was analyzed with membrane protein arrays. Lung explants were cultured in air/liquid interface with/without peptides. RESULTS: We identified 88 differentially expressed genes, including IGFBP3. Although IGFBP3 mRNA was detected in both epithelial and mesenchymal populations, the protein was restricted to the epithelium, indicating post-transcriptional regulation preventing IGFBP3 protein expression in the mesenchyme. MicroRNA profiling identified miR-34a as an IGFBP3 regulator. miR-34a was up-regulated in mesenchymal cells, and its silencing in human embryonic lung mesenchymal cells increased IGFBP3 levels. Additionally, IGFBP3 expression showed a marked downregulation from 7 to 12 pcw, suggesting its involvement in the differentiation process. The differentiation of human tip-derived lung embryonic organoids showed a drastic reduction in IGFBP3, supported by the scRNAseq data. IGFBP3 silencing in organoids activated an alveolar-like differentiation process characterized by stem cell markers downregulation and upregulation of AT2 markers. This process was mediated by TGFß signalling inhibition and BMP pathway activation. CONCLUSIONS: The IGFBP3/miR-34a axis restricts IGFBP3 expression in the embryonic undifferentiated lung epithelium, and the progressive downregulation of IGFBP3 during the pseudoglandular stage is required for alveolar differentiation.

Characterization of sexual size dimorphism in mandarin fish and association with igfbp-5a/b regulation.

Mandarin fish (Siniperca chuatsi) is an important cultured fish in East Asia that shows sexual size dimorphism (SSD), with females growing faster than males when reaching marketable size. However, the regulatory mechanism of SSD is not clear. To characterize SSD of mandarin fish and its association with gh/igf1/igfbp-5 expression, gonadal developmental atlas of the females and the males were described, and growth parameters and serum levels of E2 and T, as well as the relative expression levels of gh, igf1, and igfbp-5a/b mRNAs, were determined. The results showed that the logistic growth equation of body mass and total length of female and male were W(♀) = 667.57/(1 + e^(4.19 - 1.24*t)), W(♂) = 582.71/(1 + e^(4.07 - 1.27*t)), L(♀) = 31.47/(1 + e^1.95 - 1.08*t)), L(♂) = 26.20/(1 + e^(2.56 - 1.5*t)). The month of inflection points for body mass for females and males were 3.37 mph and 3.20 mph, respectively, when the body mass were 333.79 g and 291.36 g. The month of inflection points for total length growth were 1.80 mph and 1.70 mph, respectively, when the total length were 18.52 cm and 16.28 cm. At 1.5-2.0 mph, SSD was not clearly demonstrated. At 3.0 mph, the body mass of the females was significantly higher than that of the males (P < 0.05), Serum E2, brain gh, and liver igf1 expression of the females was significantly higher than that of the males (P < 0.05); T content of the males was significantly higher than that of the females (P < 0.05). At 4.0 months of age, the body mass of the females was highly significantly higher than that of the males (P < 0.01), Serum E2, brain gh, and liver igf1 expression of the females was highly significantly higher than that of the males (P < 0.05); T content of the males was significantly higher than that of the females (P < 0.05). With the continuous development of gonads, muscle and liver igfbp-5a and -5b expression generally tend to increase in females and males, while igfbp-5a showed a gradual increasing trend, and igfbp-5b expression showed a trend of decreasing and then increasing. Male igfbp-5a/b expression was significantly higher than female at the age of 3.0-4.0 months (P < 0.05). This work verified that the females had faster growth rate since 3.0 mph compared to the males, which may be related to higher E2 levels in females leading to higher igf1 level, through inhibition of igfbp-5a/b expression.

Association between IGF-1 and IGFBPs in Blood and Follicular Fluid in Dairy Cows Under Field Conditions.

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.

Immunomodulatory effects of the induced pluripotent stem cells through expressing IGF-related factors and IL-10 in vitro.

BACKGROUND: Induced Pluripotent Stem Cells (IPSCs) represent an innovative strategy for addressing challenging diseases, including various rheumatologic conditions. Aside from their regenerative capacities, some studies have shown the potential of these cells in the modulation of inflammatory responses. The underlying mechanisms by which they exert their effects have yet to be fully comprehended. Therefore, we aimed to explore the gene expression linked to the IGF pathway as well as IL-10 and TGF-ß, which are known to exert immunomodulatory effects. METHODS: A C57/Bl6 pregnant mouse was used for obtaining mouse embryonic fibroblasts (MEFs), then the IPSCs were induced using lentiviral vectors expressing the pluripotency genes (OCT4, SOX2, KLF1, and c-MYC). Cells were cultured for 72 h in DMEM high glucose plus leukemia inhibitory factor; Evaluating the gene expression was conducted using specific primers for Igf1, Igf2, Igfbp3, Igfbp4, Irs1, Il-10, and Tgf-ß genes, as well as SYBR green qPCR master mix. The data were analyzed using the 2-ΔΔCT method and were compared by employing the t test; the results were plotted using GraphPad PRISM software. MEFs were utilized as controls. RESULTS: Gene expression analyses revealed that Igf-1, Igf-bp3, Igf-bp4, and Il-10 were significantly overexpressed (p ≤ .01), while Igf-2 and Tgf-b genes were significantly downregulated in the lysates from IPSCs in comparison with the control MEFs. The Irs1 gene expression was not altered significantly. CONCLUSION: IPSCs are potentially capable of modulating inflammatory responses through the expression of various anti-inflammatory mediators from the IGF signaling, as well as IL-10. This discovery uncovers a previously unknown dimension of IPSCs' therapeutic effects, potentially leading to more advanced in vivo research and subsequent clinical trials.

Two-polarized roles of transcription factor FOSB in lung cancer progression and prognosis: dependent on p53 status.

BACKGROUND: Activator protein-1 (AP-1) represents a transcription factor family that has garnered growing attention for its extensive involvement in tumor biology. However, the roles of the AP-1 family in the evolution of lung cancer remain poorly characterized. FBJ Murine Osteosarcoma Viral Oncogene Homolog B (FOSB), a classic AP-1 family member, was previously reported to play bewilderingly two-polarized roles in non-small cell lung cancer (NSCLC) as an enigmatic double-edged sword, for which the reasons and significance warrant further elucidation. METHODS AND RESULTS: Based on the bioinformatics analysis of a large NSCLC cohort from the TCGA database, our current work found the well-known tumor suppressor gene TP53 served as a key code to decipher the two sides of FOSB - its expression indicated a positive prognosis in NSCLC patients harboring wild-type TP53 while a negative one in those harboring mutant TP53. By constructing a panel of syngeneically derived NSCLC cells expressing p53 in different statuses, the radically opposite prognostic effects of FOSB expression in NSCLC population were validated, with the TP53-R248Q mutation site emerging as particularly meaningful. Transcriptome sequencing showed that FOSB overexpression elicited diversifying transcriptomic landscapes across NSCLC cells with varying genetic backgrounds of TP53 and, combined with the validation by RT-qPCR, PREX1 (TP53-Null), IGFBP5 (TP53-WT), AKR1C3, and ALDH3A1 (TP53-R248Q) were respectively identified as p53-dependent transcriptional targets of FOSB. Subsequently, the heterogenous impacts of FOSB on the tumor biology in NSCLC cells via the above selective transcriptional targets were confirmed in vitro and in vivo. Mechanistic investigations revealed that wild-type or mutant p53 might guide FOSB to recognize and bind to distinct promoter sequences via protein-protein interactions to transcriptionally activate specific target genes, thereby creating disparate influences on the progression and prognosis in NSCLC. CONCLUSIONS: FOSB expression holds promise as a novel prognostic biomarker for NSCLC in combination with a given genetic background of TP53, and the unique interactions between FOSB and p53 may serve as underlying intervention targets for NSCLC.

IGFBP7 mediates oxLDL-induced human vascular endothelial cell injury by suppressing the expression of SIRT1.

Endothelial cell injury plays an important role in initiating atherosclerotic lesion formation. Insulin-like growth factor binding protein 7 (IGFBP7) is known to modulate the behaviors of tumor-associated endothelial cells. This study was conducted to test whether IGFBP7 is involved in endothelial cell injury during atherosclerosis. Oxidized low-density lipoprotein (oxLDL) treatment was used to mimic atherosclerosis-related endothelial cell apoptosis and inflammation response. Small interfering RNA (siRNA) technology was employed to deplete IGFBP7 expression in human aortic endothelial cells (HAECs). HAECs were exposed to recombinant human IGFBP7 protein to evaluate the function of IGFBP7. Notably, IGFBP7 expression in HAECs was induced by oxLDL treatment. Knockdown of IGFBP7 or treatment with anti-IGFBP7 abolished oxLDL-induced apoptosis and inflammation in HAECs. Moreover, recombinant IGFBP7 (40 ng/mL but not 25 ng/mL) promoted apoptosis and inflammation in HAECs. IGFBP7 co-localized with CD93 on the surface of HAECs. A mechanistic investigation uncovered that IGFBP7 induced endothelial cell injury through interaction with CD93 and reduction of SIRT1 expression via an autocrine manner. Overexpression of SIRT1 rescued IGFBP7-induced phenotype in HAECs. Taken together, IGFBP7 is induced by oxLDL and mediates oxLDL-induced endothelial cell apoptosis and inflammation, likely through downregulation of SIRT1. These observations support a rationale to prevent atherosclerosis by targeting IGFBP7 activity.