Insulin-like Growth Factor Binding Protein-3 Research Articles

Comparison of growth hormone stimulation tests in prepubertal children with short stature according to response to growth hormone replacement

Purpose: Growth hormone (GH) stimulation tests are essential tools for diagnosing GH deficiency (GHD). We aimed to compare L-dopa, insulin, and arginine-induced stimulation tests based on response to GH replacement.Methods: We retrospectively collected data from a review of patients who underwent the GH stimulation test. A total of 138 patients diagnosed with idiopathic short stature were categorized into group I. The remaining 135 patients, who were diagnosed with GHD and treated for 1 year, were classified into 2 subgroups: group IIa, consisting of patients with an increase of at least 0.5 in height standard deviation score (SDS), and group IIb, patients with an increase of less than 0.5 in height SDS.Results: At the initial visit, group IIa exhibited significantly lower insulin-like growth factor binding protein-3 (IGF-BP3) and higher body mass index (BMI) SDS compared to the other groups. Following 1 year of treatment, group IIb showed significantly lower height SDS, height SDS gain, growth velocity, predicted adult height SDS, weight SDS, and a higher insulin-like growth factor-1 SDS than group IIa. Bone age and IGF-BP3 were inversely associated, and BMI SDS and IGF-BP3 were positively associated with height SDS gain in GHD patients. The specificity and accuracy rates were 50.3% and 70.3% for the L-dopa-induced stimulation test, 72.3% and 86.6% for the insulin tolerance test (ITT), and 64.7% and 87.2% for the arginine-induced stimulation test (ArST).Conclusion: The ArST demonstrated lower specificity compared to the ITT. However, patients undergoing ArST experienced fewer side effects, suggesting that a careful selection of stimulation tests is crucial in diagnosing GHD.

Insulin-like Growth Factor Binding Protein-3 (IGFBP-3) measurement in the detection of significant CAD in acute chest pain patients triaged using the No Objective Testing (NOT) rule

Abstract Background After rule-out of MI in ED chest pain patients, uncertainty exists with respect to which remaining patients would benefit from objective functional/anatomical testing to detect potential underlying CAD. Using proteomics, we experimentally identified IGFBP-3 as a biomarker to assist this risk stratification and applied its measurement to >3,000 ED patients from 3 separate studies. Methods An isolated rat heart perfusate model coupled to mass spectrometry identified markers of cardiac ischemia. Human cardiac ischemia was carried out using cardiac exercise stress testing (EST, n=12). Temporal changes in IGFBP-3 during experimental MI were determined in patients undergoing septal alcohol ablation (SAA, n=12) and arterio-venous gradients of IGFBP-3 were determined from cases of proscribed cardiac catheterisation (CC, n=14). The ability of IGFBP-3 to assist clinical assessment (ROC analyses, logistic regression, C-statistic, pathways analyses) and ED risk assessment by the No Objective Testing (NOT) rule was carried out on samples from 3 prospectively recruited studies (SPACE, NZ, n=766; APACE, CH, n=1,056; FAST-TRAC, USA, n=1,230). Results IGFBP-3 identified by MS was present in perfusates of ischemic hearts only (n=3). In human cardiac EST, a delta of IGFBP-3 (∆IGFBP-3) between 0-150minutes was seen in positive ischemic tests, but not in controls (n=6 per group, p=0.026). In SAA patients, peripheral IGFBP-3 levels did not change over 24 hours (n=12, p=0.573) whereas in CC patients, significant extraction gradients of IGFBP-3 were seen across the heart and liver (p=0.013, n=14). In ED chest pain patients identified by the NOT rule (n=1,708), ΔIGFBP-3 between presentation and +2 hours (∆ IGFBP-3) was an independent logistic model predictor of unstable angina (n=123) alongside age, sex, cholesterol and Hx of CAD/MI. At 90% specificity, ∆IGFBP-3 improved the sensitivity of the model from 31% to 43%, the PPV 20% to 25% and the NPV from 94% to 95% (p=0.020). IGFBP-3 made a small improvement in "low risk" NOT rule patient identification (29% to 30%), but made a larger improvement to the ROC curve based identification in NOT rule patients for the finding of stenosis >70% on angiography (n=101, AUC clinical model = 0.682; model plus ∆ IGFBP-3 = 0.725, p=0.044). Pathways analyses (that included hs-TnT) in angiography patients (n=224) revealed ∆IGFBP-3 generated a 28% relative increase in low risk case identification (n=46 to 59). Conclusions IGFBP-3 is identified as a novel potential biomarker of cardiac ischemia, that is taken up/degraded across the heart and appears less responsive to complete infarction (MI). 0-2 hour changes in IGFBP-3 (∆ IGFBP-3) in patients identified as eligible for ED based NOT rule inclusion show promise as a useful tool to identify those with significant CAD, evidenced by the diagnosis of unstable angina, positive EST results or findings of 70% occlusion on angiography.

Insulin-like growth factor binding protein 2 predicts course of concomitant right-ventricular dilation and tricuspid regurgitation after transcatheter edge-to-edge mitral valve repair

Abstract Aims Right ventricular (RV) dilation and secondary tricuspid regurgitation (TR) are highly prevalent comorbidities in patients with mitral regurgitation and are associated with a worse prognosis. TR improvement after successful transcatheter edge-to-edge mitral valve repair (M-TEER) is reported regularly, however specific factors contributing to the recovery of RV function and TR after M-TEER are poorly understood. Particularly the role of serum biomarkers in this context is unclear. We aimed to identify specific biomarkers associated with the course of concomitant RV dilation and TR after M-TEER. Methods and Results We prospectively included 242 patients undergoing M-TEER at our center and obtained pre-procedural blood samples for biomarker analysis. A commercial multiplex protein assay (Cardiovascular III, Olink, Uppsala, Sweden) was used to quantify expression levels of 92 defined biomarkers. We then analyzed differences in biomarker expression between patients with and without right ventricular reverse remodeling (RVRR) as defined by improvement of concomitant TR by at least one grade and/or downsizing of the basal RV diameter of at least 10%. 242 patients were included in this analysis, 94 had no/mild concomitant TR at baseline, 148 had moderate/severe TR. RV diameters correlated with TR severity and were significantly larger in patients with moderate/severe TR. At baseline, expression of numerous cardiometabolic biomarkers was significantly higher in patients with moderate/severe TR. These included NT-proBNP (1.9-fold, p < 0.001), matrix metalloproteinase 2 (1.4-fold, p < 0.001) as well as insulin-like growth factor binding proteins 1 (1.7-fold, p < 0.001), -2 (1.3-fold, p = 0.001) and -7 (1.4-fold, p < 0.001). Follow-up analysis was performed in patients with initial moderate/severe TR. The course of TR and RV dimensions three months after M-TEER could be assessed in 99 patients (56 with moderate TR, 43 with severe TR). RVRR had occurred in 50 patients (50.5%). Patients without RVRR had a higher prevalence of chronic pulmonary disease (24.5 vs. 2.2%, p < 0.001). No further differences in clinical characteristics were found. Specifically, RV diameter, systolic pulmonary artery pressure (sPAP) and right-ventricular systolic function did not differ substantially between both groups. Strikingly however, the expression of insulin-like growth factor binding protein 2 (IGFBP-2) was significantly higher in patients, who did not develop RVRR (fold change 1.3 compared to patients with RVRR, p = 0.022). After adjustment for covariates IGFBP-2 was independently associated with absence of RVRR (Odds Ratio 2.078, 95% Confidence interval 1.108 – 3.897, p = 0.023). Conclusions In patients undergoing M-TEER with concomitant moderate or severe TR, numerous cardiometabolic biomarkers including IGFBP-2 are upregulated. Higher levels of IGFBP-2 at baseline are independently associated with persistent TR and/or RV dilation after M-TEER.

Assessment of experimental circulating biomarkers in volume and pressure overload: insights from a cohort study

Abstract Introduction Experimental biomarkers including Angiopoietin-2 (ANG2), bone morphogenetic protein 10 (BMP10), fibroblast growth factor 23 (FGF23), and insulin-like growth factor-binding protein 7 (IGFBP7) are hypothesized to reflect cardiac pathophysiological processes that are potentially present in adverse cardiac remodeling in volume or pressure overload. This study aims to elucidate the relationship between these circulating biomarkers and the presence of hemodynamically significant pressure or volume overload and adverse outcomes and compare it to N-terminal pro B-type natriuretic peptide (NT-proBNP). Methods We studied the association between the four experimental circulating biomarkers in patients with pressure or volume overload with reference to none/mild valvular disease in N=1302 of an observational outpatient cardiology cohort. The median age was 63.0 (25th/75th quartile 51.5, 71.4) years, 445 (34.2%) were women. Circulating biomarkers were quantified using a novel antibody-based method. Logistic regression models with cox regression plots were employed to assess the association of each biomarker with the severity of valve disease concerning volume or pressure overload, adjusted for age and sex. Results In the overall population, elevated levels of ANG2, BMP10, FGF23 and IGFB7 were positively associated with the presence of significant volume overload (ANG2: Odds ratio (OR) 1.26 (95% confidence interval (CI) 1.17-1.35), p<0.001; BMP10: OR 2.57 (CI 1.89-3.48), p<0.001; FGF23: OR 1.51 (CI 1.14-1.20), p=0.004; IGFBP7: OR 1.39 (CI 1.14-1.69), p=0.001, NT-proBNP: OR 1.69 (CI 1.47-1.95), p<0.001). No statistically significant association between circulating biomarkers and pressure overload was observed. Over a median follow-up of 4 years, 31 (20.1%) participants died in the group of volume overload and 9 (40.9%) individuals in the group of pressure overload. After multivariable-adjustment, elevated levels of BMP 10 showed a borderline association with an increased risk of all-cause mortality in individuals with volume overload compared to none/mild valvular disease: hazard ratio (HR) 1.51 (CI 0.96- 2.38), p=0.075. Higher concentrations of all biomarkers were predictive of all-cause mortality for both individuals with volume overload and those with none/mild valvular disease (ANG2: HR 3.72 (CI 1.67-8.33), p=0.001; BMP10: HR 1.65 (CI 1.20-2.26), p=0.002; FGF23: HR 2.08 (CI 1.65-2.62), p<0.001; IGFBP7: HR 1.55 (CI 1.25-1.91), p<0.001; NT-proBNP: HR 1.72 (CI 1.47-2.00), p<0.001). Conclusions This study demonstrates that circulating biomarkers involved in distinct pathophysiological pathways of inflammation, fibrosis and calcification are elevated in patients with hemodynamically significant volume overload. Since they are also related to mortality, their clinical role needs to be explored further, also in context with the routine biomarker NT-proBNP.

Apoptotic vesicles from macrophages exacerbate periodontal bone resorption in periodontitis via delivering miR-143-3p targeting Igfbp5

AbstrctBackgroundApoptotic vesicles (ApoVs), which are extracellular vesicles released by apoptotic cells, have been reported to exhibit substantial therapeutic potential for inflammatory diseases and tissue regeneration. While extensive research has been dedicated to mesenchymal stem cells (MSCs), the investigation into immune cell-derived ApoVs remains limited, particularly regarding the function and fate of macrophage-derived ApoVs in the context of periodontitis (PD).ResultsOur study corroborates the occurrence and contribution of resident macrophage apoptosis in Porphyromonas gingivalis (Pg)-associated PD. The findings unveil the pivotal role played by apoptotic macrophages and their derived ApoVs in orchestrating periodontal bone remodeling. The enrichments of diverse functional miRNAs within these ApoVs are discerned through sequencing techniques. Moreover, our study elucidates that the macrophage-derived ApoVs predominantly deliver miR-143-3p, targeting insulin-like growth factor-binding protein 5 (IGFBP5), thereby disrupting periodontal bone homeostasis.ConclusionsOur study reveals that macrophages in Pg-associated PD undergo apoptosis and generate miR-143-3p-enriched ApoVs to silence IGFBP5, resulting in the perturbation of osteogenic-osteoclastic balance and the ensuing periodontal bone destruction. Accordingly, interventions targeting miR-143-3p in macrophages or employment of apoptosis inhibitor Z-VAD hold promise as effective therapeutic strategies for the management of PD.

Nesfatin-1 expressed in human endometrial stromal cell line (THESC) stimulates decidualization through FAK/PI3K/AKT signaling pathway

This study aimed to investigate the expression and functional role of nesfatin-1, a peptide hormone traditionally associated with appetite regulation, in the human endometrium. Specifically, we examined its presence and regulatory potential in the human endometrial stromal cell line, THESC cells, focusing on the process of endometrial decidualization, which is critical for implantation and pregnancy maintenance. We found that nesfatin-1 and its binding sites were expressed in THESC cells. Furthermore, nesfatin-1 protein expression decreased after treatment with 17β- estradiol but increased upon exposure to progesterone, indicating an influence of sexsteroid hormones on nesfatin-1 expression. Notably, administration of nesfatin-1 protein to THESC cells resulted in significant upregulation of genes associated with decidualization, such as insulin-like growth factor binding protein 1 (IGFBP1) and prolactin. In addition, our research showed that nesfatin-1 promotes decidualization through the activation of the FAK/PI3K/AKT signaling pathway. These findings underscore the central role of nesfatin-1 in endometrial decidualization, and suggest its potential utility in the development of new treatments to improve fertility and pregnancy outcomes.

Clusterin from endometrial glands plays a critical role in decidualization via Trem2

BackgroundDecidualization is a critical step in establishing pregnancy in mammals. Successful decidualization depends on intricate gland-stromal crosstalk. Clusterin (Clu) is a ubiquitously secreted protein in physiological fluids that is involved in numerous physiological functions. However, the role of Clu in decidualization is not fully understood.ResultsIn this study, we examined the expression pattern of Clu during early pregnancy in mice and explored its potential function in decidualization. Our results revealed that Clu was expressed in the uterine glands on Days 1–2 of early pregnancy and on Days 5–8 during decidualization after embryo implantation, as well as in glands at the interimplantation site. Additionally, ovariectomized mice exhibited significant upregulation of Clu expression in the uterine glands 3 h after in vivo estrogen injection. Trem2, a receptor for Clu, was detected in the decidual region of mice on Days 5–8 of early pregnancy, where it mediates Clu to regulate the decidual region. Furthermore, we observed that recombinant CLU protein increased the expression of the decidualization marker molecules insulin-like growth factor binding protein 1 (IGFBP1) and prolactin (PRL) in decidual cells. However, this upregulation was not observed when Trem2 expression was inhibited with siRNA.ConclusionsUterine gland-derived Clu, a new paracrine modulator, may participate in early pregnancy by influencing the decidualization process mediated by Trem2 in mice.

High androgen level during controlled ovarian stimulation cycle impairs endometrial receptivity in PCOS patients

PCOS is one of the most common endocrine disorders among women of reproductive age. While the mechanism involved is not yet fully characterized. Our study aims to examine the pregnancy outcomes of embryo transfers in women with PCOS after pretreatment, and to explore the possible effect of high androgen levels on endometrial receptivity. Retrospective cohort study was conducted to analyze pregnancy outcomes among 2714 infertile women with tubal factor and 452 PCOS women. Endometrium samples were collected from 6 controls and 6 PCOS patients to detect the expression of endometrial receptivity marks. The implantation rate, clinical and ongoing pregnancy rates and live birth rate in women with PCOS followed fresh embryo transfers were obviously decreased even after the pretreatment. Similar pregnancy outcomes were found in frozen-thawed embryo transfer cycles between women with or without PCOS. Strikingly, serum total testosterone (TT) levels on trigger day were significantly higher in PCOS women. Women with high TT levels presented significantly lower clinical and ongoing pregnancy rates, and the expression of insulin-like growth factor binding protein 1 (IGFBP-1), and leukemia inhibitory factor (LIF) in the endometria decreased significantly as well. High doses of testosterone significantly down-regulated the expression of IGFBP-1 and LIF in Ishikawa cells. Although endocrine abnormalities had been improved before the controlled ovarian stimulation (COS) cycle started, higher serum TT levels were detected on the trigger day of the COS cycle in PCOS patients, which may contribute to the decreased fresh embryo implantation by impairing endometrial receptivity.

Insulin-Like Growth Factor Binding Protein 2 Drives Neurodegeneration in Parkinson's Disease: Insights From InVivo and InVitro Studies.

Insulin-like growth factor binding protein 2 (IGFBP2) is implicated in various neurodegenerative diseases. However, its role in Parkinson's disease (PD) is unclear. PD rat model was established by 6-OHDA injection. After 3 weeks, mRNA-seq was conducted. Rats received rIGFBP2 via intra-MFB injection 6 h prior to 6-OHDA infusion, and the effect of IGFBP2 in PD rats was investigated by western blotting, IHC, specific kits, JC-1 staining, and TUNEL analysis. Invitro, PC12 cells were treated with 6-OHDA, and CCK-8, specific kits, Hoechst 33258 staining, Western blotting, and JC-1 staining were performed to assess the IGFBP2's role. mRNA-seq revealed DEGs in PD, with attention to downregulated IGFBP2. rIGFBP2 treatment aggravated neurobehavioral deficits, decreased TH expression, Ψm, ATP level and SOD, GSH-Px activities but increased α-synuclein, ROS, MDA, mitochondrial cytochrome c contents, cell apoptosis in 6-OHDA-lesioned rats, which might be mediated through inactivating IGF-1R/AKT pathway. In 6-OHDA-treated PC12 cells, rIGFBP2 aggravated cell injury, demonstrated by decreased cell viability and increased apoptosis, oxidative stress, and mitochondrial dysfunction. Co-treatment with rIGFBP2 and rIGF-1 partially reversed the effect of rIGFBP2 on cell damage. IGFBP2 exacerbates neurodegeneration in PD through increasing oxidative stress, mitochondrial dysfunction, and apoptosis via inhibiting IGF-1R/AKT pathway.

Evaluation of potential novel biomarkers for feline hypertrophic cardiomyopathy

Hypertrophic cardiomyopathy (HCM) is the most common cardiomyopathy in cats. The diagnosis can be difficult, requiring advanced echocardiographic skills. Additionally, circulating biomarkers (N-terminal pro-B type natriuretic peptide and cardiac troponin I) have several limitations when used for HCM screening. In previous work, we identified interleukin 18 (IL-18), insulin-like growth factor binding protein 2 (IGFBP-2), brain-type glycogen phosphorylase B (PYGB), and WNT Family Member 5 A (WNT5A) as myocardial genes that show significant differential expression between cats with HCM and healthy cats. The products of these genes are released into the circulation, and we hypothesized that IL-18, IGFBP-2, PYGB, and WNT5A serum RNA and protein concentrations differ between healthy cats, cats with subclinical HCM, and those with HCM and congestive heart failure (HCM + CHF).Reverse transcriptase quantitative polymerase chain reaction (RTqPCR) and enzyme-linked immunosorbent assay (ELISA) were applied to evaluate gene and protein expression, respectively, in the serum of eight healthy controls, eight cats with subclinical HCM, and six cats with HCM + CHF. Serum IGFBP-2 RNA concentrations were significantly different among groups and were highest in cats with subclinical HCM. Compared to healthy controls, serum IL-18 and WNT5A gene expression were significantly higher in cats with HCM + CHF, and WNT5A was higher in cats with subclinical HCM. No differences were observed for PYGB.These results indicate that further investigation via large scale clinical studies for IGFBP-2, WNT5A, and IL-18 may be valuable in diagnosing and staging feline HCM.

Use of multiparametric MRI to noninvasively assess iodinated contrast-induced acute kidney injury

PurposeTo gauge the utility of multiparametric MRI in characterizing pathologic changes after iodinated contrast-induced acute kidney injury (CI-AKI) in rats. MethodsWe randomly grouped 24 rats injected with 8 g iodine/kg of body weight (n = 6 each) and 6 rats injected with saline as controls. All rats underwent T1, T2 mapping and diffusion kurtosis imaging (DKI) after contrast injection at 0 (control), 1, 3, 7, 13 days. T1, T2, and mean kurtosis (MK) values were performed in renal outer/inner stripes of outer medulla (OSOM and ISOM) and cortex (CO), and their diagnosis performance for CI-AKI also been evaluated. Serum creatinine (SCr), insulin-like growth factor-binding protein 7 (IGFBP7), tissue inhibitor metalloproteinase 2 (TIMP-2), aquaporin-1 (AQP1), α-smooth muscle actin (α-SMA), and histologic indices were examined. ResultsCompared with controls, urinary concentrations of both TIMP-2 and IGFBP7 were obviously elevated from Day 1 to Day 13 (all p < 0.05). T2 values were significantly higher than control group for Days 1 and 3, and T1 and MK increased were more remarkable at all time points (Days 1–13) in CI-AKI (all p < 0.05) than control group. Changes in T1 and MK strongly correlated with renal injury scores of all anatomical compartments and with expression levels of AQP1 and moderately correlated with α-SMA. Changes in T2 values correlating moderately with renal scores of CO, ISOM and OSOM and AQP1. The MK obtained the highest area under the receiver operating characteristic (ROC) curve of 0.846 with a sensitivity of 70.8 % and specificity of 88.9 %. ConclusionsCombined use of multiparametric MRI could be a valid noninvasive method for comprehensive monitoring of CI-AKI. Among these parameters, MK may achieve the best diagnostic performance for CI-AKI.

Low-temperature-induced disruption of reproductive axis and sperm vitality via stress axis in Monopterus albus

The ricefield eel (Monopterus albus) is inherently timid and highly sensitive to stress. Our previous studies have shown that low-temperature weather could significantly affect the sperm vitality of ricefield eels. This study aims to investigate the regulatory mechanism of low-temperature effects on testicular function and sperm vitality in ricefield eels. The ricefield eels were initially reared at low (10 °C) and normal (25 °C) temperatures for 24 h. Low temperatures were found to induce the expression of pituitary pro-opiomelanocortin (POMC) and testes insulin-like growth factor-binding protein 1 (IGFBP1) mRNA expression, suggesting that the reduction in sperm vitality could be attributed to the activation of the stress axis. Moreover, the results indicated a significant decrease in sperm occupancy and count in the testes, along with a reduced percentage of motile sperm. Subsequent transcriptome analysis showed substantial inhibition of reproductive hormone genes (gnrh1, lh, and fsh) in the brain and pituitary, and downregulation of meiosis-related genes (dmc1, rec8, and sycp3) in the testes. These findings suggest that low temperatures might disrupt testicular development and spermatogenesis by inhibiting the reproductive axis. Metabolomics analysis then demonstrated a significant reduction in the levels of metabolites related to glycolysis, fatty acid metabolism, and the tricarboxylic acid (TCA) cycle in the testes after low-temperature treatment. Interestingly, the expression of zona pellucida sperm-binding proteins 3 and 4 (ZP3 and ZP4), which may affect sperm vitality and spermatogenesis, was significantly induced by low temperatures in the testes. In conclusion, these findings suggested that low temperatures might affect testicular function and sperm vitality by simultaneously activating the stress axis and inhibiting the reproductive axis and energy metabolism in the testes.

Early pregnancy exposure to Microcystin-LR compromises endometrial decidualization in mice via the PI3K/AKT/FOXO1 signaling pathway

Previous experimental studies have found that exposure to Microcystin-leucine arginine can impact pregnancy outcomes in female mice. The impact of MC-LR on early pregnancy in mammals is not yet well understood. Both mice and humans need to undergo decidualization to maintain pregnancy. In this study, we tried to evaluate whether MC-LR affects decidualization process in mice. Our research showed that MC-LR decreased maternal weight gain, uterine weight, and implantation site weight. These findings suggested that MC-LR exerted adverse effects on decidualization. In mice, we examined decreased number of polyploid decidual cells, but marked proliferation of mouse endometrial stromal cells the expression levels of prolactin (PRL)and insulin-like growth factor binding protein 1 (IGFBP1) were significantly downregulated in the decidual tissue and primary endometrial stromal cells following MC-LR treatment. Furthermore, further in vitro experiments identified that MC-LR promoted endometrial stromal cell division and cycle transition. Lastly, our study demonstrated that MC-LR impaired decidualization through the PI3K/AKT/FOXO1 pathway. Collectively, these data suggested that exposure to MC-LR impaired decidualization during early pregnancy.

Acyl-CoA long-chain synthetase 1 (ACSL1) protects the endometrium from excess palmitic acid stress during decidualization

Endometrial receptivity relies on the functional and morphological change of endometrium stromal cells (EnSCs) and epithelial cells in the secretory phase. Decidualization of ESCs and transitions in endometrium epithelial cells are crucial for successful uterine implantation and maintaining pregnancy. Accumulated data have demonstrated that decidualization is tightly coordinated by lipid metabolism. However, the lipidomic change and regulatory mechanism in uterine decidualization are still unknown. Our study showed that endometrium stromal cells and decidual stromal cells had different lipidomic profiles. Acyl-CoA long-chain synthetase 1 (ACSL1) which converts fatty acids to acyl-CoA expression was strongly elevated during decidualization. ACSL1 knockdown inhibited stromal-to-decidual cell transition and decreased the decidualization markers prolactin and Insulin-like growth factor-binding protein-1 (IGFBP1) expression through the AKT pathway. Lipid uptake was upregulated in stromal cells while lipid droplet accumulation was downregulated during decidualization. Meanwhile, silencing of ACSL1 led to impaired spare respiratory capacity, and downregulation of TFAM expression, indicating robust lipid metabolism. While palmitic acid addition impeded decidualization, overexpression of ACSL1 could partially reverse its effect. ACSL inhibitor Triacsin C significantly impeded decidualization in a three-dimensional coculture model consisting of endometrial stromal cells and epithelial cells. Knockdown of ACSL1 in stromal cells decreased the expression of the decidualization markers PAEP and SPP1 in epithelial cells. Collectively, ACSL1 is essential for uterine decidualization and protects stromal cells from excess palmitic acid stress.

The inhibitory effect of type V transforming growth factor-β receptor antagonist on the proliferation of keloid fibroblasts by suppressing insulin-like growth factor-binding protein 3-interleukin-6 signaling

Abstract Background: Hyperplasia of fibroblasts is critical in keloid pathogenesis. Insulin-like growth factor-binding protein 3 (IGFBP3) is an important factor in the regulation of cell growth and type V transforming growth factor-β receptor (TβR-V) is a specific receptor of IGFBP3. However, the role of IGFBP3 in keloid development has not been reported. Objectives: This study aimed to investigate the role of IGFBP3 in keloid pathogenesis and evaluate the effects of TβR-V antagonist on keloid fibroblasts (KFs) activities. Methods: IGFBP3 expression in keloids and its impact on KF proliferation were examined. The effects of TβR-V antagonist on KF cell proliferation, migration, and invasion were also investigated. Differentially expressed genes (DEGs) between TβR-V antagonist treated and nontreated KFs were identified through RNA-sequencing (RNA-seq), followed by Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and protein–protein interaction (PPI) network analyses. Results: IGFBP3 was overexpressed in keloids and could promote KF proliferation. TβR-V antagonist suppressed KFs proliferation, migration, and invasion. GO and KEGG analyses showed that the downregulated DEGs revealed by RNA-seq were significantly enriched in terms related to cell proliferation. Interleukin-6 (IL-6) was identified as the only gene interacting with IGFBP3 in the PPI network and was associated with nine hub genes. In vitro assay confirmed the suppression of IL-6 by TβR-V antagonist in KFs. Conclusion: Our study demonstrated that TβR-V antagonist could inhibit keloid growth likely through suppressing IGFBP3-IL-6 signaling activation. These findings suggest that targeting TβR-V could be a potential therapeutic strategy for keloid treatment.

Establishment of IGF-1 and IGFBP-3 continuous reference percentiles from data of healthy children using three kinds of immunoassay systems

Background and aimsAppropriate continuous reference intervals (RIs) for serum insulin-like growth factor 1 (IGF-1) and insulin-like growth factor-binding protein 3 (IGFBP-3) are important for diagnosing growth hormone deficiency or excess. Material and methodsWe retrospectively reviewed serum IGF-1 and IGFBP-3 levels in Korean children aged 0–17 years who were diagnosed as healthy during a short stature workup in the outpatient clinics of three hospitals. IGF-1 and IGFBP-3 levels were measured using various immunoassays, including Liaison XL for IGF-1, an immunoradiometric assay (IRMA) for IGFBP-3 (n = 5522), and Immulite 2000 (n = 3036) and cobas e801 (n = 314). We established RIs from the 2.5th to 97.5th percentile RI curves using the lambda–mu–sigma (LMS) method for each sex group. ResultsPediatric serum continuous IGF-1 and IGFBP-3 reference percentiles by LMS method were found to be immunoassay method-dependent, but aligned relatively well with the manufacturers’ RIs. IGFBP-3 levels displayed notable discrepancies among the different immunoassay methods. ConclusionAge- and sex-specific pediatric LMS based continuous reference intervals are method dependent and they should be calculated for dynamic parameters that show variations throughout childhood.

Latent stem cell-stimulating radially aligned electrospun nanofibrous patches for chronic tympanic membrane perforation therapy

Chronic tympanic membrane (TM) perforation is a tubotympanic disease caused by either traumatic injury or inflammation. A recent study demonstrated significant progress in promoting the regeneration of chronic TM perforations through the application of nanofibers with radially aligned nanostructures and controlled release of growth factors. However, radially aligned nanostructures with stem cell-stimulating factors have never been used. In this study, insulin-like growth factor binding factor 2 (IGFBP2)-incorporated radially aligned nanofibrous patches (IRA-NFPs) were developed and applied to regenerate chronic TM perforations. The IRA-NFPs were prepared by electrospinning 8 wt% polycaprolactone in trifluoroethanol and acetic acid (9:1). Random nanofibers (RFs) and aligned nanofibers (AFs) were successfully fabricated using a flat plate and a custom-designed circular collector, respectively. The presence of IGFBP2 was confirmed via Fourier transform infrared spectroscopy and the release of IGFBP2 was sustained for up to 20 days. In vitro studies revealed enhanced cellular proliferation and migration on AFs compared to RFs, and the incorporation of IGFBP2 further promoted these effects. Quantitative real-time PCR revealed mRNA downregulation, correlating with accelerated migration and increased cell confluency. In vivo studies showed IGFBP2-loaded RF and AF patches increased regeneration success rates by 1.59-fold and 2.23-fold, respectively, while also reducing healing time by 2.5-fold compared to the control. Furthermore, IGFBP2-incorporated AFs demonstrated superior efficacy in healing larger perforations with enhanced histological similarity to native TMs. This study, combining stem cell stimulating factors and aligned nanostructures, proposes a novel approach potentially replacing conventional surgical methods for chronic TM perforation regeneration. Statement of significanceChronic otitis media (COM) affects approximately 200 million people worldwide due to inflammation, inadequate blood supply, and lack of growth factors. Current surgical treatments have limitations like high costs and anesthetic risks. Recent research explored the use of nanofibers with radially aligned nanostructures and controlled release of growth factors to treat chronic tympanic membrane (TM) perforations. In this study, insulin-like growth factor binding protein 2 (IGFBP2)-incorporated radially aligned nanofibrous patches (IRA-NFPs) were developed and applied to regenerate chronic TM perforations. We assessed their properties and efficacy through in vitro and in vivo studies. IRA-NFPs showed promising healing capabilities with chronic TM perforation models. This innovative approach has the potential to improve COM management, reduce surgery costs, and enhance patient safety.

Insulin-like growth factor-binding protein 7 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.

IGFBP2 functions as an endogenous protector against hepatic steatosis via suppression of the EGFR-STAT3 pathway

ObjectiveNon-alcoholic fatty liver disease (NAFLD) is deemed as an emerging global epidemic, whereas the underlying pathogenic mechanism remains to be clarified. We aimed to systemically analyze all the NAFLD-related gene expression datasets from published human-based studies, by which exploring potential key factors and mechanisms accounting for the pathogenesis of NAFLD. MethodsRobust rank aggregation (RRA) method was used to integrate NAFLD-related gene expression datasets. For fatty liver study, adeno-associated virus (AAV) delivery and genetic knockout mice were used to create IGFBP2 (Insulin-like growth factor binding protein 2) gain- or loss-of function models. Western blot, Co-immunoprecipitation (Co-IP), immunofluorescent (IF) staining, luciferase assay, molecular docking simulation were performed to reveal the IGFBP2-EGFR-STAT3 axis involved. Key axis protein levels in livers from healthy donors and patients with NAFLD were assessed via immunohistochemical staining. ResultsBy using RRA method, the present study identified IGFBP2 being the most significantly down-regulated gene in all NAFLD subjects. The decreased IGFBP2 expression was further confirmed in the liver tissues from patients and animal models of NAFLD. IGFBP2 deficiency aggravated hepatic steatosis and NASH phenotypes and promoted lipogenic gene expression both in vivo and in vitro. Mechanistically, IGFBP2 directly binds to and regulates EGFR, whereas blockage of the IGFBP2-EGFR complex by knockdown of IGFBP2 resulted in the EGFR-STAT3 pathway activation, which in turn promoted the promoter activity of Srebf1. By using molecular docking simulation and protein-protein interaction analysis, the sequence of 233-257 amino acids in IGFBP2 was characterized as a key motif responding for its specific binding to EGFR and the protective effect against hepatic steatosis. ConclusionsThe current study has, for the first time, identified IGFBP2 as a novel protector against hepatosteatosis. The protective effect is mediated by its specific interaction with EGFR and thereby suppressing the EGFR-STAT3 pathway. Therefore, pharmaceutically targeting the IGFBP2-EGFR-STAT3 axis may provide a theoretical basis for for the treatment of NAFLD/NASH and the associated diseases.

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

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). 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. Four hundred ninety-three subjects underwent GH provocation testing for investigation of short stature to exclude GHD during the study period. Fifty-one children hada 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. 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 thenormal 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.