Insulin-like Growth Factor Binding Protein-3 Research Articles

Distinct Urinary Proteome Changes Across Estimated Glomerular Filtration Rate Stages in a Cohort of Black South Africans.

Kidney function parameters including estimated glomerular filtration rate (eGFR) and urine albumin excretion are commonly used to diagnose chronic kidney disease (CKD). However, these parameters are relatively insensitive, limiting their utility for screening and early detection of kidney disease. Studies have suggested that urinary proteomic profiles differ by eGFR stage, offering potential insights into kidney disease pathogenesis alongside opportunities to increase the sensitivity of current testing strategies. In this study, we characterized and compared the urinary proteome across different eGFR stages in a Black African cohort from rural Mpumalanga Province, South Africa. We stratified 81 urine samples by eGFR stage (mL/min/1.73 m2): Stage G1 (eGFR ≥ 90; n = 36), Stage G2 (eGFR 60-89; n = 35), and Stage G3-G5 (eGFR < 60; n = 10). Urine proteomic analysis was performed using an Evosep One liquid chromatography system coupled to a Sciex 5600 TripleTOF in data-independent acquisition mode. Nonparametric multivariate analysis and receiver operating characteristic (ROC) curves were used to assess the performance of differentially abundant proteins (DAPs). Pathway analysis was performed on DAPs. Creatinine-based eGFR was calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation. In this study, thirty-eight urinary proteins were differentially abundant for eGFR Stages 3-5 when compared to Stages G1 (AUC = 0.95; CI: 0.86-1) and G2 (AUC = 0.84; CI: 0.64-0.98). Notably, only six urinary proteins (Cystatin M (CST6), glutathione hydrolase 6 (GGT6), sushi domain containing 2 (SUSD2), insulin-like growth factor binding protein 6 (IGFBP6), heat shock protein 90 beta family member 1 (HSP90B1), and mannosidase alpha class 1A member 1 (MAN1A1)) were differentially abundant when comparing Stage G1 and Stage G2 with a modest AUC = 0.81 (CI: 0.67-0.92). Pathway analysis indicated that DAPs were associated with haemostasis and fibrin clot formation. In a rural cohort from South Africa, the urinary proteome differed by eGFR stage, and we identified six differentially abundant proteins which, in combination, could help to differentiate earlier eGFR stages with higher predictive accuracy than the currently available tests.

IGFBP2 ATTENUATES RESTRAIN STRESS-INDUCED ANXIETY-LIKE BEHAVIOR VIA MODULATING THE MYELINATION AND SYNAPTIC PLASTICITY IN THE MEDIAL PREFRONTAL CORTEX

BackgroundExposure to stress markedly impairs the emotional functions of the highly evolved prefrontal association cortex (PFC). However, the underlying molecular mechanisms are poorly understood and limited options for treatment. Our previous study has found that the level of IGFBP2 in serum is related to stress resilience in individuals. Insulin-like growth factor binding protein 2 (IGFBP2), a neurotrophic factor, has been associated with neurite outgrowth and synaptic plasticity in central nervous system, enhancing stress resilience.AimTo examine the protective effects of IGFBP-2 on stress related disorder and explore its mechanism in SD rats and provide new targets for the intervention.MethodHere, using a model of restrain stress (RS), we found that RS induces obvious anxiety-like behavior in the open field (OFT) and elevated plus maze test (EPM). RNA-sequencing was further applied to analyze the molecular mechanisms of mPFC following RS. Then we injected IGFBP2 by tail vein administrations to evaluate the anxiolytic effect of IGFBP2. Immunofluorescence and electron microscopy experiments were applied to verify the effect of IGFBP2 on RS-induced brain structural and functional abnormalities.ResultRS enhances susceptibility to anxiety-like behavior in rats, with injured myelination in mPFC. Systemic delivery of IGFBP2 significantly attenuated anxiety-like behavior in OFT and EPM. Besides, IGFBP2 treatment rats showed enhanced myelination of axons compared to controls. To further confirm the pro-myelinating function of IGFBP2, lysolecithin-induced rat model of focal demyelination was used. Our results showed that IGFBP2 treatment was sufficient to attenuate anxiety-like behaviors and promote remyelination in lysolecithin-induced rat model of focal demyelination. In addition, the RS rats treated with IGFBP2 significant increase in the thickness and length of PSD.Discussion & ConclusionCollectively, our results demonstrate that the ultrastructural and functional changes of myelin and synaptic alterations in mPFC could be involved in stress-induced anxiety-like behavior. Notably, our study provides the first evidence that systemic delivery of IGFBP2 produced rapid-acting effects in rescuing the anxiety like behavior in RS rat models, which provides a critical rationale about IGFBP2 may has therapeutic potential for the treatment of anxiety disorders from a translational perspective clinically and deserves further study to provide more evidence for the treatment of anxiety disorder in the future.

IGFBP5 regulates fibrocartilage differentiation and cartilage injury induced by T-2 toxin via blocking IGF-1/IGF-1R signalling.

Kashin-Beck disease (KBD) is a form of osteoarthropathy that affects the skeletal and joint systems of children and adolescents. Insulin-like growth factor binding protein 5 (IGFBP5) plays an important role in bone growth and development. This study aimed to investigate the role of IGBFP5 in regulating the function and differentiation of chondrocytes in KBD. The mRNA and protein expressions of IGFBP5, IGF-1 and IGF-1R were detected by RT-qPCR and western blot assays. Commercial kits were performed to measure the mitochondrial ROS content, calcium loading and ATP synthesis in chondrocytes. 3-(4,5-Dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay was used to detect the cell viability of chondrocytes. Co-IP and pull-down assays were conducted to verify the binding activity of IGFBP5 to IGF-1R. The rat KBD model was constructed by a low selenium diet and T-2 toxin. The expression of IGFBP5 was upregulated in KBD patient and rat tissues. Further studies showed that interfering with IGFBP5 effectively inhibited T-2-induced chondrocyte damage and mitochondrial stress. IGFBP5 depressed the interaction between IGF-1 and IGF-1R, thereby affecting the regulation of IGF-1/IGF-1R signalling in the repair of chondrocytes. In addition, the fibrous differentiation of cartilage progenitor cells (CPCs) and the activity and migration of CPCs induced by T-2 stimulation were suppressed under IGFBP5 silence treatment. IGFBP5 was upregulated during the pathological progression of KBD, and IGFBP5 competitively bound with IGF-1R to impede the interactions between IGF-1 and IGF-1R. Knockdown of IGFBP5 inhibited fibrotic differentiation and ameliorated the reduction of CPC function in KBD model.

Association between Insulin-Like Growth Factor Binding Protein-7 and Heart Failure.

Heart failure (HF), a widespread public health issue, affects about 26 million people all around the world, and its incidence and prevalence are still growing. Measuring serum biomarkers is beneficial in diagnosing HF and evaluating its prognosis. During the previous decade, various investigations have focused on identifying new HF biological markers that would have additional and/or superior prognostic, diagnostic, or classification value. While heart-specific biological markers, such as atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP), are commonly applied in clinical practice, there is still an unmet need for new markers in HF management. Insulin-like growth factor-binding protein-7 (IGFBP7), a cellular senescence marker, has been considered as a candidate biomarker in HF. This study aims to comprehensively reveal the underlying mechanism connecting IGFBP-7 to HF and review studies evaluating the prognostic or diagnostic performance of IGFBP-7 in combination with or in contrast with other potential HF biological markers. Increased IGFBP7 levels are associated with a set of functional and structural heart abnormalities such as diastolic dysfunction. Increased IGFBP7 concentrations seem to be an indicator of cardiac overload or injury and are related to HF major risk factors, including atherosclerosis, diabetes, and renal function. IGFBP7 is predictive of short and long-term outcomes in the HF population and can independently predict the rate of hospitalization and HF-related mortality.

Innovating Glioma Therapy Using Secretions from Umbilical Cord Mesenchymal Stem Cells to Target Homeobox and Growth Factor Genes.

Background: Glioblastoma is a prevalent and challenging malignant brain tumor. Secretome therapy using human umbilical cord mesenchymal stem cells (hUCMSCs) appears to be a promising treatment for glioblastoma. This study analyzed the potential of the hUCMSC secretomes (hUCMSCs-sec) for glioma therapy. Materials and Methods: Characterization of hUCMSCs was performed by examining certain markers, including CD44, CD90, CD105, CD73, CD13, CD19, CD14, CD45, CD34, and HLA-D. The cells' ability to differentiate into adipocytes, chondrocytes, and osteocytes was evaluated. Cytotoxic effect on Glioblastoma (GBM) cells was analyzed using 2-[2-methoxy-4-nitrophenyl]-3-[4-nitrophenyl]-5-[2,4-disulfophenyl]-2H-tetrazolium (WST-8). mRNA relative expression, including homeobox (HOXA5, HOXB1, HOXC9 and HOXC10), insulin-like growth factor binding protein 2 (IGFBP2), Extracellular signal-regulated kinases (ERK), Epidermal growth factor receptor (EGFR), and Caspase 3 (Casp3), were quantified by quantitative Reverse Transcription Polymerase Chain Reaction (qRT-PCR). Results: The hUCMSCs-sec was successfully isolated and identified, showing positive markers and its capacity to differentiate into chondrocytes, adipocytes, and osteocytes. hUCMSCs-sec exerted a cytotoxic effect on GBM cells and upregulated the expression of Casp3, whereas it decreased the expression of HOX, IGFBP2, EGFR, and ERK in GBM cells. Conclusion: The secretomes from hUCMSCs show potential for GBM cell therapy by improving the deregulation of HOX, inducing apoptosis, and inhibiting cell proliferation genes.

Differential Expression of BCL2 and IGFBP2 in Childhood Immune Thrombocytopenic Purpura Clinical Subtypes: Implications for Predicting Disease Progression and Apoptotic Regulation.

Immune thrombocytopenic purpura (ITP), which poses challenges in treatment response, is an autoimmune-mediated bleeding disorder with an extremely complex pathogenesis and unpredictable clinical progression. Dysregulation of apoptotic pathways may influence both the pathogenesis and prognosis of ITP. This study aimed to evaluate the expression patterns of the apoptotic protein insulin-like growth factor-binding protein 2 (IGFBP2) and the anti-apoptotic protein B-cell lymphoma 2 (BCL2) as potential predictive or prognostic biomarkers for disease progression in childhood ITP. The expression levels of BCL2 and IGFBP2 were assessed in peripheral blood samples from 40 pediatric ITP patients and 30 age- and sex-matched healthy controls using enzyme-linked immunosorbent assays. Plasma levels of BCL2 and IGFBP2 were higher in ITP patients than in control subjects. Although the difference in IGFBP2 expression was not statistically significant (p = 0.910), BCL2 expression was significantly elevated (p < 0.001). Notably, chronic ITP patients had significantly lower levels of both IGFBP2 and BCL2 markers compared to patients who achieved spontaneous recovery (p < 0.001). BCL2 and IGFBP2 appear to be promising noninvasive biomarkers for predicting disease outcomes in newly diagnosed ITP, emphasizing the need for validation in large-scale, multicenter longitudinal studies.

MRI-Based Evaluation of Pituitary Size and Volume in Children with Idiopathic Growth Hormone Deficiency.

Growth hormone deficiency (GHD) is the most common cause of pathological short stature of endocrine origin. Among the causes of pathological short stature, pathologies in the hypothalamic-pituitary region, especially the pituitary gland, have an important place, and imaging the region with pituitary magnetic resonance imaging (MRI) is a frequently used method in the diagnosis process and guides the diagnosis and treatment process. It is known that hypoplasia or aplasia of the pituitary gland, which plays a role in the synthesis and release of many hormones in addition to GH, causes short stature. This study aims to evaluate pituitary size and volume as potential diagnostic markers in children with idiopathic growth hormone deficiency (IGHD) compared with healthy controls. The study included children who presented to our hospital's pediatric endocrinology outpatient clinic with complaints of short stature/growth retardation and was diagnosed with IGHD, for whom MRI of the pituitary had been performed. Pituitary MRI examinations were retrospectively reviewed to measure the, adenohypophysis height, anterior-posterior diameter, width, and volume, and these measurements were compared with those of an age- and gender-matched control group. A total of 55 patients diagnosed with IGHD were included, with a mean chronological age of 9.8 ± 3.4 years, of whom 58.2% (n = 32) were male. The control group consisted of 42 healthy children with a mean chronological age of 9.3 ± 3.4 years, with 47.6% (n = 20) being male. No significant differences in age and gender were found between the groups (P = 0.523, P = 0.306, respectively). Although the adenohypophysis height, anterior-posterior diameter, width, and volume of patients with IGHD were lower than those in the control group, no statistical differences were observed between the two groups (P > 0.05). There were no differences in pituitary size and volume based on gender in either group (P > 0.05). A positive correlation was found between pituitary height, width, and volume with age, insulin-like growth factor-1 (IGF-1) standard deviations (SD), and insulin-like growth factor binding protein-3 (IGFBP-3) SD (P < 0.05), whereas no correlation was found between stimulated peak GH levels and pituitary size and volume (P > 0.05). We found that the size and volume of the adenohypophysis in patients with IGHD are not different from those of healthy peers; however, they showed a correlation particularly with IGF-1 and IGFBP-3 standard deviations.

Large-Scale Plasma Proteomics Profiles for Predicting Ischemic Stroke Risk in the General Population.

We aimed to develop and validate a protein risk score for ischemic stroke (IS) risk prediction and to compare its predictive capability with IS clinical risk factors and IS polygenic risk score. The prospective cohort study included 53 029 participants from UKB-PPP (UK Biobank Pharmaceutical Proteomics Project). IS protein risk score was calculated as the weighted sum of proteins selected by the least absolute shrinkage and selection operator regression. The discrimination ability of models was assessed by C statistic. IS risk factors included age, sex, smoking, waist-to-hip ratio, antihypertensive medication use, systolic and diastolic blood pressure, coronary heart disease, diabetes, total cholesterol/high-density lipoprotein cholesterol ratio, and estimated glomerular filtration rate. Polygenic risk score was computed using identified susceptibility variants. After exclusions, 38 060 participants from England were randomly divided into the training set and the internal validation set in a 7:3 ratio, and 4970 participants from Scotland/Wales were assigned as the external validation set. Of 43 030 participants included (mean age, 59.0 years; 54.0% female), 989 incident IS occurred during a median follow-up of 13.6 years. In the training set, IS protein risk score was constructed using 17 out of 2911 proteins. In the internal validation set, compared with the basic model (age and sex: C statistic,0.720 [95% CI, 0.691-0.749]), IS protein risk score had the highest predictive performance for IS risk (C statistic, 0.765 [95% CI, 0.736-0.793]), followed by clinical risk factors of IS (C statistic, 0.753 [95% CI, 0.725-0.781]), and IS polygenic risk score (C statistic, 0.730 [95% CI, 0.701-0.759]). The top 5 proteins with the largest absolute coefficients in the IS protein risk score, including GDF15 (growth/differentiation factor 15), PLAUR (urokinase plasminogen activator surface receptor), NT-proBNP (N-terminal pro-B-type natriuretic peptide), IGFBP4 (insulin-like growth factor-binding protein 4), and BCAN (brevican core protein), contributed most of the predictive ability of the IS protein risk score, with a cumulative C statistic of 0.761 (95% CI, 0.733-0.790). These results were verified in the external validation cohort. A simple model, including age, sex, and the IS protein risk score (or only the top 5 proteins) had a good predictive performance for IS risk.

Comparison of growth hormone therapy response according to the presence of growth hormone deficiency in children born small for gestational age with short stature in Korea: a retrospective cohort study

BackgroundThis study aimed to compare the response to growth hormone (GH) therapy according to the presence of GH deficiency (GHD) in short-stature children born small for gestational age (SGA) in Korea and to present appropriate GH dose criteria.MethodsWe evaluated 27 children born SGA with short stature and GHD (GHD group) and 23 without GHD (non-GHD group) registered in the LG Growth Study. Growth responses and changes in GH dose over a 2-year GH therapy period were compared, and the factors affecting growth response were investigated.ResultsThe standard deviation scores (SDSs) for baseline weight and body mass index (BMI) were significantly lower in boys without GHD than in boys with GHD. The SDS for insulin-like growth factor-1 (IGF-1) was lower among boys without GHD than among boys with GHD, while the SDS for insulin-like growth factor-binding protein-3 (IGFBP-3) was higher among girls without GHD than among girls with GHD; however, there was no significant difference when comparing all children with GHD to those without GHD. Regardless of the presence of GHD, the difference between chronological age and bone age decreased annually. Notably, there was significantly rapid bone age progression among patients without GHD. The findings showed differences in GH dose according to GHD starting from the 2nd year of therapy, with the non-GHD group receiving a significantly higher dose. Regarding the factors affecting growth response, younger age and bone age, higher height SDS, BMI SDS and MPH SDS were related to higher growth response (Δheight SDS and Δgrowth velocity), but there was no statistically significant correlation.ConclusionGHD is rare among children born SGA. Nonetheless, if there are any signs of decreased growth velocity or hypopituitarism, the presence of GHD should be assessed before GH therapy, and personalized therapy based on the results is required.

Abstract A014: Mitochondrial dynamics in insulin-like growth factor binding protein 3-mediated radiosensitivity of oral squamous cell carcinoma cells

Abstract Radiation therapy, a common adjuvant therapy for oral squamous cell carcinoma (OSCC) patients either received operation or not, efficiently reduces the tumor infiltration area and growth. Insulin-like growth factor binding protein 3 (IGFBP3) is a member of a secretary glycoprotein family. We previously found that IGFBP3 promotes cell migration and lymph node metastasis of OSCC cells. However, OSCC patients with high IGFBP3 expression had a better prognostic outcome than those with low IGFBP3 expression. Moreover, we verified that ectopic expression of IGFBP3 augmented the radiosensitivity, while IGFBP3 knockdown diminished the radio-resistance of OSCC cells. We observed changes in mitochondrial morphology in IGFBP3-expressing OSCC cells after ionizing radiation (IR) treatment; however, the roles of IGFBP3 in mitochondrial dynamics remain unclear. The analyses of cell survival, reactive oxygen species production, and loss of mitochondrial membrane potential were used to verify the IGFBP3-mediated radiosensitivity. Using mitochondria by 3D cell explorer and quantification of mitochondria dynamics by immunofluorescence staining, the fission and fusion mitochondria in irradiated IGFBP3-expressing cells and IGFBP3 knockdown cells were increased, respectively. By western blot, we found phosphorylated dynamin-related protein 1 (DRP1) positively associated with IGFBP3 levels in irradiated cells. By transiently expressing DRP1 in IGFBP3-expressing cells, we found that IGFBP3-mediated radiosensitivity and mitochondrial fission were flattened by DRP1 inhibition, suggesting the role of DRP1 in IGFBP3-mediated mitochondrial fission. Our study is to elucidate the mechanism of IGFBP3-mediated radiosensitivity and hope to provide different strategies to sensitize radiotherapy and enhance the synergy between radiotherapy and immunotherapy. Citation Format: Ya-Wen Chen. Mitochondrial dynamics in insulin-like growth factor binding protein 3-mediated radiosensitivity of oral squamous cell carcinoma cells. [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Translating Targeted Therapies in Combination with Radiotherapy; 2025 Jan 26-29; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(2_Suppl):Abstract nr A014

P2Y1R-IGFBP2 signaling: new contributor to astrocyte-neuron communication.

In a recent article published in Nature Communications (Shigetomi et al Nat Commun 15(1):6525, 2024), Shigetomi et al. identified that upregulated astrocytic purinergic P2Y1 receptors (P2Y1R), acting via the downstream molecule, insulin-like growth factor binding protein 2 (IGFBP2), play a crucial role in neuronal hyperexcitability. In epilepsy and stroke models, P2Y1R-IGFBP2 signaling was found to mediate astrocyte-driven neuronal hyperexcitability and so is a new contributor to astrocyte-neuron communication. Thus, IGFBP2 could be an alternative target for treating the effects of upregulated P2Y1R activity in reactive astrocytes in neurological diseases.

Identification of IGFBP3 and LGALS1 as potential secreted biomarkers for clear cell renal cell carcinoma based on bioinformatics analysis and machine learning.

Clear cell renal cell carcinoma (ccRCC) is the most common subtype of renal cell carcinoma (RCC). Due to the lack of symptoms until advanced stages, early diagnosis of ccRCC is challenging. Therefore, the identification of novel secreted biomarkers for the early detection of ccRCC is urgently needed. This study aimed to identify novel secreted biomarkers for diagnosing ccRCC using bioinformatics and machine learning techniques based on transcriptomics data. Differentially expressed genes (DEGs) in ccRCC compared to normal kidney tissues were identified using 3 transcriptomics datasets (GSE53757, GSE40435 and GSE11151) from the Gene Expression Omnibus (GEO). Potential secreted biomarkers were examined within these common DEGs using a list of human secretome proteins from The Human Protein Atlas. The recursive feature elimination (RFE) technique was used to determine the optimal number of features for building classification machine learning models. The expression levels and clinical associations of candidate biomarkers identified with RFE were validated using transcriptomics data from The Cancer Genome Atlas (TCGA). Classification models were then developed based on the expression levels of these candidate biomarkers. The performance of the models was evaluated based on accuracy, evaluation metrics, confusion matrices, and ROC-AUC (receiver operating characteristic-area under the ROC curve) curves. We identified 44 DEGs that encode potential secreted proteins from 274 common DEGs found across all datasets. Among these, insulin-like growth factor binding protein 3 (IGFBP3) and lectin, galactoside-binding, soluble, 1 (LGALS1) were selected for further analysis using the RFE technique. Both IGFBP3 and LGALS1 showed significant upregulation in ccRCC tissues compared to normal tissues in the GEO and TCGA datasets. The results of the survival analysis indicated that patients with higher expression levels of these genes exhibited shorter overall and disease-free survival times (OS and DFS). Decision tree and random forest models based on IGFBP3 and LGALS1 levels achieved an accuracy of 98.04% and an AUC of 0.98. This study identified IGFBP3 and LGALS1 as promising novel secreted biomarkers for ccRCC diagnosis.

Insulin and Insulin-like Growth Factor and Risk of Postmenopausal Estrogen Receptor-Positive Breast Cancer: A Case-Cohort Analysis.

Higher concentration of insulin-like growth factor-1 (IGF-1) increases postmenopausal breast cancer risk, but evidence for insulin and c-peptide is limited. Furthermore, not all studies have accounted for potential confounding by biomarkers from other biological pathways, and not all were restricted to estrogen receptor (ER)-positive breast cancer. This was a case-cohort study of 1,223 postmenopausal women (347 with ER-positive breast cancer) from the Melbourne Collaborative Cohort Study. We measured insulin, c-peptide, IGF-1, insulin-like growth factor binding protein-3, and biomarkers of inflammatory and sex-steroid hormone pathways. Poisson regression with a robust variance estimator was used to estimate risk ratios (RR) and 95% confidence intervals (95% CI) for ER-positive breast cancer per doubling plasma concentration and for quartiles, without and with adjustment for other, potentially confounding biomarkers. ER-positive breast cancer risk was not associated with doubling of insulin (RR = 0.97, 95% CI, 0.82-1.14) or c-peptide (RR = 1.01, 95% CI, 0.80-1.26). Risk seemed to decrease with doubling IGF-1 (RR = 0.80, 95% CI, 0.62-1.03) and insulin-like growth factor binding protein-3 (RR = 0.62, 95% CI, 0.41-0.90). RRs were not meaningfully different when exposures were modeled as quartiles. RRs were less than unity but imprecise after adjustment for inflammatory and sex-steroid hormone biomarkers. Circulating insulin, c-peptide, and IGF-1 were not positively associated with risk of ER-positive breast cancer in this case-cohort analysis of postmenopausal women. Associations between insulin and c-peptide and risk of ER-positive breast cancer in postmenopausal women are likely to be weak.

Role and mechanism of IGFBP5 in the real-ambient particulate matter exposure-induced chronic lung injury.

Inflammation and oxidative stress are the main pathological processes of particulate matter (PM)-induced lung injury. Insulin-like growth factor binding protein 5 (IGFBP5) is an important secretory protein related to inflammation and oxidative damage in several tissues, whereas its roles in PM-induced lung adverse effects remain largely unexplored. In the present study, mice were housed in an individual ventilated cage (IVC)-based real-ambient PM exposure system for eight weeks. Transcriptomics was employed to analyze gene expression alterations. IGFBP5 was significantly downregulated after PM exposure. Functional investigations demonstrated that IGFBP5 downregulation exacerbated PM-induced oxidative damage, as evidenced by elevated levels of reactive oxygen species (ROS) and malondialdehyde, as well as decreased levels of superoxide dismutase 2 (SOD2). Conversely, IGFBP5 overexpression effectively rescued these oxidative stress phenotypes. Mechanistically, IGFBP5 downregulation attenuated extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation, thereby impairing SOD2 catalytic activity and amplifying ROS accumulation. Co-treatment with si-IGFBP5 and ERK1/2 signaling pathway inhibitor PD98059 could further aggravate the production of ROS in cells. Moreover, microRNAs (miRNAs) are an important class of gene expression regulators. We found that the upregulated hsa-miR-33a-5p repressed IGFBP5 translation by forming a silencing complex with Argonaute protein 2 (AGO2) in a real-ambient PM exposure system, which further led to the suppression of the ERK1/2-SOD2 signaling pathway and increased levels of ROS. This study revealed that the downregulation of IGFBP5 promoted oxidative damage in lung cells by inhibiting the IGFBP5-ERK1/2-SOD2 pathway, and targeted inhibition of hsa-miR-33a could alleviate PM-induced lung injury by upregulating IGFBP5.

Correlation of Body Mass Index with Serum Osteocalcin and Insulin-Like Growth Factor Binding Protein-3 in the Assessment of Pubertal Growth Spurt - A Comparative Study.

Body Mass Index (BMI) percentiles have a bearing on skeletal maturation. The correlation of BMI with serum osteocalcin (OC) and insulin-like growth factor binding protein-3 (IGFBP-3) and cervical vertebral maturation (CVM) assumes even greater importance in orthodontic treatment planning for skeletal Class II jaw discrepancies. The aim of the study was thus to estimate BMI percentiles, serum OC, and IGFBP-3 and correlate it with CVM to assess the opportune pubertal growth spurt. Height and body weight were measured to the BMI percentiles of the study participants with skeletal class II malocclusion (n = 51, age 11-18 yrs). Lateral cephalometry was used for CVM staging. Blood was collected to quantitatively assess the serum OC and IGFBP-3 levels using Sandwich-ELISA. Obesity was more common in females compared to males (24% vs. 7.69%) while the reverse was true for underweight (4% vs. 15.39%). The majority of the obese participants belonged to CVM4-CVM6. Mean OC and IGFBP-3 were the highest in the obese category (71.879 ± 5.275 ng/mL, 55.541 ± 5.795 ng/mL). No statistically significant difference was observed in the mean OC and IGFBP-3 levels between males and females (64.993 ± 10.929 ng/mL vs. 58.795 ± 23.054 ng/mL, P = 0.231: 44.030 ± 12.767 ng/mL vs. 48.081 ± 10.843 ng/mL, P = 0.229). The clinical relevance of serum biomarkers (OC, IGFBP-3) and their correlation with BMI percentile and CVM stages could be certainly used to assess the circumpubertal growth status. Obese and severely obese females, though they belong to the age range of 13-17 years and later CVM stages, there was a significant increase in OC and IGFBP-3 serum levels that could be used to plan orthopedic treatment.

Integration of Gastric Cancer RNA-Seq Datasets Along With PPI Network Suggests That Nonhub Nodes Have the Potential to Become Biomarkers.

The breakthrough discovery of novel biomarkers with prognostic and diagnostic value enables timely medical intervention for the survival of patients diagnosed with gastric cancer (GC). Typically, in studies focused on biomarker analysis, highly connected nodes (hubs) within the protein-protein interaction network (PPIN) are proposed as potential biomarkers. However, this study revealed an unexpected finding following the clustering of network nodes. Consequently, it is essential not to overlook weakly connected nodes (nonhubs) when determining suitable biomarkers from PPIN. In this study, several potential biomarkers for GC were proposed based on the findings from RNA-sequencing (RNA-Seq) datasets, along with differential gene expression (DGE) analysis, PPINs, and weighted gene co-expression network analysis (WGCNA). Considering the overall survival (OS) analysis and the evaluation of expression levels alongside statistical parameters of the PPIN cluster nodes, it is plausible to suggest that THY1, CDH17, TGIF1, and AEBP1, categorized as nonhub nodes, along with ITGA5, COL1A1, FN1, and MMP2, identified as hub nodes, possess characteristics that render them applicable as biomarkers for the GC. Additionally, insulin-like growth factor (IGF)-binding protein-2 (IGFBP2), classified as a nonhub node, demonstrates a significant negative correlation with both groups within the same cluster. This observation underscores the conflicting findings regarding IGFBP2 in various cancer studies and enhances the potential of this gene to serve as a biomarker. The findings of the current study not only identified the hubs and nonhubs that may serve as potential biomarkers for GC but also revealed a PPIN cluster that includes both hubs and nonhubs in conjunction with IGFBP2, thereby enhancing the understanding of the complex behavior associated with IGFBP2.

Urinary biomarkers for diagnosing acute kidney injury in sepsis in the emergency department.

Development of acute kidney injury (AKI) in patients with sepsis is associated with increased mortality, highlighting the importance of early detection and management. However, baseline creatinine or urine output measurements are required for AKI diagnosis, which can be challenging in emergency departments (EDs). We aimed to evaluate the association between urinary biomarkers and the AKI diagnosis or 30-day survival status in patients with sepsis in the ED. This prospective observational study enrolled patients from a single ED. We enrolled adult patients presenting to the ED with symptoms suggestive of infection and an initial quick sequential organ failure assessment score ≥2. Initial urine samples were collected, and urinary biomarkers (dickkopf-3, soluble triggering receptor expressed on myeloid cells-1, kidney injury molecule-1, neutrophil gelatinase-associated lipocalin (NGAL), and tissue inhibitor of metalloproteinases-2 (TIMP-2), and insulin-like growth factor binding protein-7 (IGFBP-7), and TIMP-2×IGFBP-7) were analyzed using an enzyme-linked immunosorbent assay kit. Multivariable logistic regression models were used to evaluate biomarker performance. Of 84 patients, 63 (75.0%) were diagnosed with AKI and 16 (19.0%) died within 30 days. None of the urinary biomarkers demonstrated significant differences between the survivors and non-survivors. NGAL (p=0.014) and TIMP-2×IGFBP-7 (p=0.027) levels were different between the AKI and non-AKI groups. The multivariable logistic regression model suggested a higher area under the receiver operating characteristic curve for models, including TIMP-2×IGFBP-7 (from 0.853 to 0.889, p=0.018). None of the urinary biomarkers in the initial urine sample demonstrated an independent association with AKI diagnosis or 30-day survival status in patients with sepsis presenting to the ED. Further studies with larger population are necessary to confirm its clinical utility and explore its role.

Matrix Metalloproteinases, Tissue Inhibitors of Metalloproteinases, and Their Ratios in Women with Polycystic Ovary Syndrome and Healthy Controls.

Matrix metalloproteinases (MMPs) are M2 macrophage markers that are modulated by inflammation. A disintegrin and metalloproteinases (ADAMS) and those with thrombospondin motifs (ADAMTS) regulate the shedding of membrane-bound proteins, growth factors, cytokines, ligands, and receptors; MMPs, ADAMS, and ADAMTS may be regulated by tissue inhibitors of metalloproteinases (TIMPs). This study aimed to determine whether these interacting proteins were dysregulated in PCOS. A Somascan proteomic analysis of 12 MMPs, three of their inhibitors (TIMP-1, 2, 3), two ADAMS (9, 12), five ADAMTS (1, 4, 5, 13, 15), insulin-like growth factor binding protein-1 (IGFBP-1), and insulin-like growth factor-1 (IGF-1) was undertaken in a well-validated PCOS database of 143 women with PCOS and 97 controls. Women with PCOS had significantly higher levels of MMP-9 and lower levels of MMP-2, MMP-14, TIMP-2, IGFBP-1, and IGF-1 compared to the controls (p < 0.0001, p < 0.005, p < 0.04, p < 0.05, p < 0.0001, and p < 0.0001, respectively). No differences were observed for any other MMPs. The ADAMS or ADAMTS levels did not differ between groups. Body mass index (BMI) was correlated with MMP-9 (p < 0.01), MMP-1 (p < 0.05), MMP-2 (p < 0.05), MMP-10 (p < 0.005), MMP-12 (p < 0.005), ADAM-9 (p < 0.05), and IGFBP-1 (p < 0.0001), but only MMP-9 still differed after accounting for BMI. MMP-9/TIMP-1, MMP-9/TIMP-2, and MMP-9/TIMP-3 ratios were higher in the PCOS group (p < 0.01), whilst MMP-17/TIMP-1 and MMP-17/TIMP-2 were lower (p = 0.01). MMP-2/TIMP ratios showed no difference between groups. TIMP-2 was positively correlated with CRP (p < 0.01). MMP changes in PCOS are largely driven by BMI, though increased MMP-9 is BMI-independent, suggesting that any deleterious effects of MMP-9 would be potentially exacerbated by a concomitantly increased BMI. The significant increases in the MMP-9/TIMP ratios suggests MMP-9 overactivity in PCOS.

Ablation of IGFBP5 expression alleviates neurogenic erectile dysfunction by inducing neurovascular regeneration.

To investigate the therapeutic potential of eliminating insulin-like growth factor-binding protein 5 (IGFBP5) expression in improving erectile function in mice with cavernous nerve injury (CNI)-induced erectile dysfunction (ED). Eight-week-old male C57BL/6 mice were divided into four groups: a sham-operated group and three CNI-induced ED groups. The CNI-induced ED groups were treated with intracavernous injections 3 days before the CNI procedure. These injections included phosphate-buffered saline, scrambled control short hairpin RNA (shRNA), or shRNA targeting mouse IGFBP5 lentiviral particles. One week after CNI, erectile function was evaluated and the penile tissue was then harvested for histological examination and western blot analysis. Additionally, the major pelvic ganglia (MPG) and dorsal root ganglia (DRG) were cultured for ex vivo neurite outgrowth assays. Following CNI, IGFBP5 expression in the cavernous tissues significantly increased, reaching its peak at day 7. First, ablation of IGFBP5 expression promotes neurite sprouting in MPG and DRG when exposed to lipopolysaccharide. Second, ablating IGFBP5 expression in CNI-induced ED mice improved erectile function, likely owing to increased neurovascular contents, including endothelial cells, pericytes, and neuronal processes. Third, ablating IGFBP5 expression in CNI-induced ED mice promoted neurovascular regeneration by increasing cell proliferation, reducing apoptosis, and decreasing Reactive oxygen species production. Finally, western blot analysis demonstrated that IGFBP5 ablation attenuated the JNK/c-Jun signaling pathway, activated the PI3K/AKT signaling pathway, and increased vascular endothelial growth factor and neurotrophic factor expression. Ablating IGFBP5 expression enhanced neurovascular regeneration and ultimately improved erectile function in CNI-induced ED mice.

In situ Detection of Insulin-Like Growth Factor-1, Insulin-Like Growth Factor-Binding Protein-3, and Leptin in Human Placental and Immature Fetus Tissues

Background: Gestational hypertension (HTN) can impair fetal growth and development. The purpose of this study was to look at the histological changes and level of expression of insulin-like growth factor-1 (IGF-1), IGF-binding protein-3 (IGFBP-3), and leptin in placental and fetal tissue from women with pregnancy HTN. Methods: Collection of tissue biopsy samples was from 60 women and divided into four groups: placenta-positive control (normal birth), placenta-negative control (a prior abortion), placenta and fetus (from dilation and curettage procedures), and miscarried placentas and fetuses from pregnancies exacerbated by high pressure. Histological and immunohistochemical markers for IGF-1, IGFBP-3, and leptin were done. Results: Women with gestational HTN had significant tissue alterations in their placentas, including increasing blood vessel thickness, fibrinoid exudate, chorangiosis, villus hypovascularization, and stromal fibrinoid necrosis. Immunohistochemical examination demonstrated a significant link between HTN and increased expression of IGF-1, IGFBP-3, and leptin, with greater expression in the HTN group than in the control group. Conclusion: Pregnancy HTN causes histological changes in the placenta, which may lead to poor fetal outcomes. The abnormal regulation of IGF-1, IGFBP-3, and leptin in the placenta and fetal tissues of women with HTN implies that these development factors may play a role in predicting and controlling high blood pressure-related births.