Insulin-like Growth Factor Binding Protein-3 Research Articles

Potential diagnostic marker gene set for non-alcoholic steatohepatitis associated hepatocellular carcinoma with lymphocyte infiltration.

Non-alcoholic steatohepatitis (NASH), a prominent driver of hepatocellular carcinoma (HCC) besides virus and alcohol, induces a series of complex liver structural and immune microenvironment changes, which make the early diagnosis and treatment of NASH-associated HCC (NASH-HCC) more challenging. This study aims to identify signature genes and explore the role of immune cell infiltration in NASH-HCC to improve early detection and prognosis assessment. Differential gene and immune cell infiltration are important indicators for predicting the progress of oncology and responsiveness of tumor patients to immunotherapy, usually confirmed through biopsy tests with poor patient compliance. To obtain a highly correlated signature gene set and validate immune cell infiltration status, the GSE164760 and GSE102079 datasets from the Gene Expression Omnibus (GEO) database were analyzed using machine learning algorithms. Feature genes were identified based on differentially expressed genes and key modular genes identified by weighted gene co-expression network analysis (WGCNA). The signature genes were screened using the least absolute shrinkage and selection operator (LASSO), random forest, and support vector machine recursive feature elimination (SVM-RFE) machine learning algorithms. Subsequently, the signature genes were subjected to diagnostic efficacy tests, gene set enrichment analysis, immune cell infiltration assessment and real-time reverse transcription polymerase chain reaction (RT-qPCR) validation. Six signature genes were identified, including C-C motif chemokine ligand 14 (CCL14), C-type lectin domain family 4 member G (CLEC4G), ficolin-2 (L-ficolin, FCN2), insulin-like growth factor binding protein 3 (IGFBP3), C-X-C motif chemokine ligand 14 (CXCL14), and vasoactive intestinal polypeptide type I receptor (VIPR1). The area under the receiver operating characteristic (ROC) curve for the six signature genes was between 0.927-0.958, and the calibration curves also indicated that they had high prediction accuracy. Six signature genes were positively associated with NASH pathological process pathways including butyric acid metabolism and fatty acid degradation. The infiltration of immune cells such as M2-type macrophages was significantly positively correlated with the signature genes. RT-qPCR revealed a significant decrease in the expression of CLEC4G and IGFBP3 in the NASH-HCC model. CLEC4G and IGFBP3 hold potential as biomarkers for clinical surveillance, offering new insights for early detection and prognosis evaluation.

Urine TIMP2.IGFBP7 Reflects Kidney Injury After Moderate Volume Paracentesis in Patients With Ascites: A Randomized Control Study.

Urinary biomarkers may predict acute kidney injury (AKI) in cirrhosis with ascites in a moderate volume paracentesis setting. The study aimed to assess the risk and consequence of AKI and its progression in patients with decompensated cirrhosis undergoing paracentesis using a urine test measuring tissue inhibitor of metalloproteinases-2 (TIMP2) and insulin-like growth factor-binding protein 7 (IGFBP7). A randomized, controlled trial was performed. All outpatients with decompensated cirrhosis with ascites and diuretic complications were enrolled and randomized into 3 and 5 L paracentesis groups. Serial urine samples were analyzed for TIMP2. IGFBP7 concentration before and after paracentesis. A total of 90 patients with decompensated cirrhosis were consecutively enrolled during the study period. After screening, 29 patients were enrolled in the 3-L paracentesis group, and 25 patients were enrolled in the 5-L paracentesis group. The mean of the MELD score was 8 ± 1.2. Urine TIMP2.IGFBP7 > 2, rising urine TIMP2, and rising urine TIMP2/urine Cr were shown in patients within the 5-L group for 48% (p = 0.015), 32% (p = 0.049), and 76% (p = 0.010) respectively, indicating a higher incidence of renal tubular injury markers in this group. Urine TIMP2.IGFBP7/1000 > 2 was statistically significant to predict a hemodynamic event (p = 0.002). In cirrhotic patients with ascites undergoing paracentesis, a 5-L paracentesis volume was associated with a higher incidence of renal tubular injury markers. Trail Registration: The national clinical registration number was TCTR20191116003.

Using urinary tissue inhibitor of metalloproteinase-2 and insulin like growth factor binding protein-7 as biomarkers of acute kidney injury in elderly Egyptian patients with sepsis

Background Several trials have assessed the usefulness of various biomarkers in the early detection and risk assessment of acute kidney injury (AKI). Tissue inhibitor of metalloproteinase (TIMP-2) and insulin like growth factor binding protein-7 are two of these indicators. Both are produced and released by renal tubular cells and implicated in G1 cell cycle arrest during the early stages of cellular stress or injury caused by diverse stressors. This study aimed to assess the Predictive and diagnostic value of these biomarkers for AKI in elderly Egyptian patients with sepsis. Patients and methods The study was performed in Alexandria Main University Hospital, Intensive Care Unit and Internal Medicine Department, Geriatric Unit. The study was performed on 150 patients. All patients aged 65 years or older had sepsis. Patients with chronic kidney disease, a history of renal transplantation, patients admitted with AKI, and with hospital stays less than 24 h were excluded. Results There was a statistically significant association between tissue inhibitor of metalloproteinase-2 and insulin-like growth factor binding protein-7 for the prediction of AKI. It can be used for early detection and diagnosis of AKI in septic elderly Egyptian patients with P less than 0.001.

Bevacizumab, tislelizumab and nab-paclitaxel for previously untreated metastatic triple-negative breast cancer: a phase II trial

BackgroundOptimal first-line therapy for metastatic triple-negative breast cancer (mTNBC) varied in different situations. This phase II trial explores the efficacy and safety of combination regimens with bevacizumab, tislelizumab and nab-paclitaxel...

Alzheimer's disease-related cortical proteins modify the association of brain insulin signaling with cognitive decline.

BackgroundBrain insulin signaling has been associated with both Alzheimer's disease (AD) pathology and cognitive decline, but the mechanisms remain unclear.ObjectiveTo examine whether AD-related cortically-expressed proteins modify the association of brain insulin signaling and cognitive decline.MethodsParticipants included 116 autopsied members of the Religious Orders Study (58 with diabetes matched to 58 without, by age at death, sex, and education) who had both postmortem brain (prefrontal cortex) insulin signaling (by ELISA and immunohistochemistry, including RAC-alpha serine/threonine-protein kinase or AKT1) and AD-related cortical protein measurements. Levels of five AD-related proteins including insulin-like growth factor-binding protein-5 (IGFBP-5) and inositol-tetrakisphosphate 1-kinase (ITPK1) were measured using quantitative proteomics. We conducted adjusted linear mixed model analyses to examine associations of insulin signaling measures and AD-related proteins with longitudinally assessed cognitive function.ResultsHigher levels of IGFBP-5 and lower levels of ITPK1 were each associated with higher levels of AKT1 phosphorylation (pT308AKT1 /total AKT1). Additionally, higher levels of AKT1 phosphorylation were associated with faster decline in global cognition and most cognitive domains. IGFBP-5 partially mediated the association of AKT1 phosphorylation with the decline rate of global cognition and cognitive domains including perceptual speed and visuospatial abilities. Further, ITPK1 had an interaction with AKT1 phosphorylation on decline of global cognition and domains including episodic memory, perceptual speed, and visuospatial abilities.ConclusionsAD-related proteins IGFBP-5 and ITPK1 are each associated with insulin signaling AKT1 phosphorylation in the postmortem human brain. Moreover, IGFBP-5 mediates, while ITPK1 moderates, the association between AKT1 phosphorylation and late-life cognitive decline.

PROGNOSTIC VALUE OF URINARY TISSUE INHIBITOR OF METALLOPROTEINASE-2 (TIMP-2) AND INSULIN-LIKE GROWTH FACTOR BINDING PROTEIN 7 (IGFBP-7) FOR CONTRAST-INDUCED ACUTE KIDNEY INJURY: A LITERATURE REVIEW

Relevance: Contrast-induced acute kidney injury (CI-AKI) is a serious complication of medical procedures using contrast agents. Despite the decrease in the incidence of acute kidney injury (AKI), CI-AKI remains one of the leading causes of renal function deterioration, especially in emergencies. Serum creatinine (SCr) is not a reliable biomarker for early diagnosis since its level increases only when more than 50% of renal mass is lost. Modern iodinated contrast agents (ICA) reduce the risk of AKI but remain dangerous for patients with chronic kidney disease (CKD) and diabetes.The study aimed to summarize published studies of TIMP-2 and IGFBP-7 early biomarkers to improve the diagnosis and prognosis of contrast-induced acute kidney injury.Methods: The sources were searched in Pubmed, Web of Science, and Cochrane databases. The review included 21 sources published from 2014 to 2025.Results: Iodized contrasts are widely used in clinical procedures. They increase the risk of CI-AKI, with intensive therapy remaining the only supportive measure. [TIMP-2]·[IGFBP7] biomarkers predict the development of severe AKI (KDIGO stage 2/3), mortality, and AKI severity with high sensitivity and accuracy. Elevated levels of these biomarkers are associated with the risk of death or dialysis within 9 months, making them useful for close patient monitoring.Conclusion: Recent studies have highlighted the importance of early diagnosis of CI-AKI using IGFBP-7 and TIMP-2 biomarkers, which is important for early intervention and improved treatment outcomes. Further studies will help improve the understanding and management of this complication, considering risk factors such as creatinine levels, diabetes, and heart failure. The need for safe and effective methods for diagnosing and preventing CI-AKI is relevant both in Kazakhstan and abroad. Careful monitoring of high-risk patients and tailoring AKI management to individual patient needs can improve clinical practice and reduce the incidence of end-stage kidney failure.

Plasma Insulin-like Growth Factor-Binding Protein-7 Is Positively Associated with Age, Obesity, Mortality, and Cancer in Postmenopausal Women.

Predictors of premature death and cancer development are needed to more precisely identify individuals who may warrant preventive intervention. Circulating insulin-like growth factor (IGF)-binding protein-7 (IGFBP7) and, to a lesser extent, the IGFBP7/IGF-1 ratio are emerging biomarkers of renal and cardiovascular morbidity. However, their relationships with aging, obesity, mortality, and cancer risk remain unclear. This hypothesis-generating study investigated plasma IGFBP7, IGF-1, and their ratio as predictors of all-cause mortality and the incidence of any cancer (excluding nonmelanoma skin cancer), obesity-related cancer (composite of 13 cancer types), and breast cancer in a large longitudinal cohort of postmenopausal women. We assessed the relationships of each biomarker with age, body mass index, and each outcome (bivariately and controlling for age, body mass index, race, physical activity, education, income, marital status, alcohol intake, smoking, diabetes, and hormone therapy) in 793 Women's Health Initiative Observational Study participants (mean, 19.4-year follow-up). In adjusted analyses, IGFBP7 increased with age and obesity and was positively associated with risks of all-cause mortality [HR = 2.42 (95% confidence interval, 1.37-4.26); P = 0.002], any cancer [HR = 2.04 (1.05-3.94); P = 0.035], and obesity-related cancer [HR = 1.58 (0.99-2.51); P = 0.053]. Also in adjusted analyses, the IGFBP7/IGF-1 ratio increased with age and was positively associated with all-cause mortality [HR = 1.51 (1.14-1.99); P = 0.004] and any cancer incidence [HR = 5.44 (1.13-26.1); P = 0.034]. Plasma IGFBP7 and the IGFBP7/IGF-1 ratio are positively associated with age, obesity (IGFBP7 only), mortality, and cancer in postmenopausal women. Plasma IGFBP7 may represent an age- and obesity-sensitive biomarker of increased risk of developing cancer and/or dying prematurely.

Alveolar epithelial type 2 cell specific loss of IGFBP2 activates inflammation in COVID-19

The coronavirus disease 2019 (COVID-19) global pandemic is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, our understanding of SARS-CoV-2-induced inflammation in alveolar epithelial cells remains very limited. The contributions of intracellular insulin-like growth factor binding protein-2 (IGFBP2) to SARS-CoV-2 pathogenesis are also unclear. In this study, we have uncovered a critical role for IGFBP2, specifically in alveolar epithelial type 2 cells (AEC2), in the immunopathogenesis of COVID-19. Using bulk RNA sequencing, we show that IGFBP2 mRNA expression is significantly downregulated in primary AEC2 cells isolated from fibrotic lung regions from patients with COVID-19-acute respiratory distress syndrome (ARDS) compared to those with idiopathic pulmonary fibrosis (IPF) alone or IPF with a history of COVID-19. Using multicolor immunohistochemistry, we demonstrated that IGFBP2 and its selective ligands IGF1 and IGF2 were significantly reduced in AEC2 cells from patients with COVID-ARDS, IPF alone, or IPF with COVID history than in those from age-matched donor controls. Further, we demonstrated that lentiviral expression of Igfbp2 significantly reduced mRNA expression of proinflammatory cytokines—Tnf-α, Il1β, Il6, Stat3, Stat6 and chemokine receptors—Ccr2 and Ccr5—in mouse lung epithelial cells challenged with SARS-CoV-2 spike protein injury (S2; 500 ng/mL). Finally, we demonstrated higher levels of cytokines—TNF-α; IL-6 and chemokine receptor—CCR5 in AEC2 cells from COVID-ARDS patients compared to the IPF alone and the IPF with COVID history patients. Altogether, these data suggest that anti-inflammatory properties of IGFBP2 in AEC2 cells and its localized delivery may serve as potential therapeutic strategy for patients with COVID-19.Graphical

IGF1 Signaling Regulates Neuropeptide Expression in Hypothalamic Neurons Under Physiological and Pathological Conditions.

Insulin-like growth factor 1 (IGF1) plays a critical role in metabolism and aging, but its role in the brain remains unclear. This study examined whether hypothalamic neurons respond to IGF1 and how its actions are modulated. RT-qPCR and single-cell RNA sequencing indicated that Igf1r mRNA is expressed in neuropeptide Y/Agouti-related peptide (NPY/AgRP) neurons but has higher expression in pro-opiomelanocortin (POMC) neurons. IGF1 binding proteins Igfbp3 and Igfbp5 were significantly expressed, whereby Igfbp5 levels were modulated by fasting, nutrient availability, and circadian rhythms, implying that IGF1 signaling can be controlled by multiple mechanisms. In mouse and human models, IGF1 regulated Agrp, Npy, Pomc, Cartpt, Spx, Gal, and Fam237b expression, producing an overall anorexigenic profile. Hyperinsulinemia induced IGF1 resistance, accompanied by reduced IGF1R protein, as well as Igf1r and Irs2 mRNA expression via over-activation of phosphoinositide 3-kinase/forkhead box O1 (PI3K-FOXO1) signaling. Thus, hypothalamic neurons respond to IGF1 under physiological conditions, and hyperinsulinemia is a novel mechanism that drives cellular IGF1 resistance.

Circ_0044362 Facilitates the Progression of Epithelial Ovarian Cancer via Enhancing HOXB4 Transcription to Activate the RUNX1/IGFBP3 Axis.

Increasing numbers of studies have elucidated the emerging roles of circular RNA (circRNA) in cancer progression. However, the function of circRNAs in modulating their parental genes in ovarian cancer remains poorly understood. In this study, we identified that circ_0044362, a circRNA derived from homeobox B4 (HOXB4), significantly promotes the expression of its parental gene HOXB4 in ovarian cancer. Functionally, circ_0044362 promotes the malignant phenotypes of ovarian cancer cells. Further analysis revealed that circ_0044362 facilitates the transcriptional activation of its parental gene HOXB4 by directly guiding U1 small nuclear ribonucleoprotein (snRNP) to its promoter region, thereby enhancing the oncogenic behaviors of ovarian cancer cells. Furthermore, HOXB4 positively regulates runt-related transcription factor 1 (RUNX1) expression, with RUNX1 serving as a transcription factor to promote the transcription of insulin-like growth factor binding protein-3 (IGFBP3). Notably, inhibitors of either HOXB4, RUNX1, or IGFBP3 could reverse the oncogenic activity mediated by circ_0044362. Collectively, our findings reveal the involvement of the circ_0044362/HOXB4 pathway in ovarian cancer progression and provide potential therapeutic strategies for ovarian cancer treatment.

Insulin-like growth factor binding protein-3 (IGFBP-3): a biomarker of coronary artery disease induced myocardial ischaemia.

Among individuals presenting to the emergency department (ED) with chest pain, clinical uncertainty surrounds the appropriate identification of non-myocardial infarction (MI) individuals who would most benefit from objective functional/anatomical testing (e.g. imaging). We applied a proteomic biomarker discovery approach to identify novel candidates reflecting coronary artery disease (CAD) induced ischaemia that could translate to measurement in clinical samples. Mass spectroscopy (MS) of perfusate from an isolated rat heart model of cardiac ischaemia identified >100 novel protein biomarkers. A prominent candidate, insulin-like growth factor binding protein (IGFBP-3), was then interrogated for its ability to identify CAD-related ischaemia (e.g. positive cardiac stress test; unstable angina pectoris, UAP; arterial stenosis >70% on angiography) in multiple patient sample sets [cardiac stress testing, n = 12; septal alcohol ablation (SAA), n = 12; ED chest pain, n = 2977]. In cardiac stress testing, a significant delta IGFBP-3 (ΔIGFBP-3) between 0 and 150 min was seen in positive, but not negative, tests (P = 0.03). In SAA, peripheral IGFBP-3 levels did not change over 24 h (P = 0.57). In ED patients, ΔIGFBP-3 between 0 and 2 h (i) identified more 365-day low-risk major adverse cardiac event cases (27-30%), (ii) provided 7% improvement in positive predictive value over a clinical model for the identification of unstable angina (P = 0.01), and (iii) was a significant, independent predictor of >70% stenosis on angiography, improving indeterminate risk prediction by 9% (95% CI 3-15%). Our discovery approach has translated IGFBP-3 as a potential biomarker to identify significant CAD/ischaemia in patients who do not meet diagnostic thresholds for MI.

The effects of urine alkalinization on kidney function in critically ill patients with COVID-19: a proof-of-concept randomized clinical trial

BackgroundAcute kidney injury (AKI) is a common complication of COVID-19. While the exact mechanisms remain unclear, direct viral infection of renal tubular epithelial cells is hypothesized. Given the pH-dependent entry of coronaviruses into host cells, urine alkalinization was proposed as a potential preventive strategy.MethodsThis was a proof-of-concept prospective, randomized clinical trial in critically ill patients with COVID-19. Patients were randomized to urine alkalinization versus usual care. The intervention group received intravenous 8.4% sodium bicarbonate to achieve a urine pH ≥ 7.5 up to 10 days after randomization. The primary outcome was the proportion of patients achieving target urine pH. Secondary outcomes included changes in urine tissue inhibitor of metalloproteinases-2 (TIMP-2) and insulin-like growth factor-binding protein 7 (IGFBP7), AKI development, renal replacement therapy, and adverse effects.ResultsThe trial was terminated early due to slow recruitment and the end of the COVID-19 pandemic. Sixteen patients were enrolled (median age 48 years old, 75% male). More patients in the intervention group achieved target urine pH than in the control group (75% vs 37.5%, P = 0.315). There was a separation of urine pH between both groups throughout 10 days (P = 0.097 for interaction). However, the intervention did not significantly impact urine [TIMP-2]x[IGFBP7] concentrations (P = 0.813 for interaction) or clinical outcomes, including AKI occurrence (risk ratio 0.6 (95% confidence interval 0.21, 1.70), P = 0.619). More patients in the intervention group experienced hypernatremia and metabolic alkalosis. Notably, patients with elevated urine [TIMP-2]x[IGFBP7] concentrations and AKI had higher ICU and 60-day mortality.ConclusionsWhile urine alkalinization is feasible and can increase urine pH, we could not demonstrate differences in AKI rates or changes in urine [TIMP-2]x[IGFBP7] concentrations in critically ill COVID-19 patients.

Biomarkers of cell cycle arrest, microcirculation dysfunction, and inflammation in the prediction of SA-AKI

Sepsis-associated acute kidney injury (SA-AKI) is a severe complication in critically ill patients, with a complex pathogenesis involving in cell cycle arrest, microcirculatory dysfunction, and inflammation. Current diagnostic strategies remain suboptimal. Therefore, this study aimed to evaluate pathophysiology-based biomarkers and develop an improved predictive model for SA-AKI. The prospective observational study was conducted, enrolling 26 healthy individuals and 96 sepsis patients from Peking University Third Hospital. Clinical and laboratory data were collected, and patients were monitored for AKI development within 72 h. Further, sepsis patients were categorized into SA-noAKI (n = 46) and SA-AKI (n = 50) groups. Novel biomarkers, including tissue inhibitor of metalloproteinase-2 (TIMP-2), insulin-like growth factor-binding protein-7 (IGFBP-7), and angiopoietin-2 (Ang-2), were measured in all participants. Among these sepsis patients, the SA-AKI incidence was 52.08% (50/96). Compared to SA-noAKI, the SA-AKI group had significantly higher levels of TIMP-2 (93.55 [79.36, 119.56] ng/mL), IGFBP-7 (27.8 [21.44, 37.29] ng/mL), TIMP-2×IGFBP-7 (2.91 [1.90, 3.55] (ng/mL)²/1000), and Ang-2 (10.61 [5.79, 14.57] ng/mL) (P < 0.05). Accordingly, logistic regression identified TIMP-2×IGFBP-7 (OR = 2.71), Ang-2 (OR = 1.19), and PCT (OR = 1.05) as independent risk factors. The ROC curve of the predictive model demonstrated superior early-stage accuracy (AUC = 0.898), which remained stable during internal validation (AUC = 0.899). Meanwhile, the nomogram exhibited that this model was characterized with excellent discrimination, calibration, and clinical performance. In general, TIMP-2×IGFBP-7, Ang-2 and PCT were the independent risk factors for SA-AKI, and the novel model based on the three indicators provided a more accurate and sensitive strategy for the early prediction of SA-AKI.

Insulin like growth factor binding protein 7 activate JNK/ERK signaling to aggravate uranium-induced renal cell cytotoxicity.

Acute kidney injury (AKI) can occur primarily by exposing kidneys to uranium (U). Insulin-like growth factor binding protein 7 (IGFBP7) can regulate sepsis-induced AKI and epithelial-mesenchymal transition through ERK1/2 signaling. In vitro, the IGFBP7's role and mechanism of action in uranium-induced NRK-52E cells, however, remains unknown. To evaluate the effect of U exposure on kidneys, rat kidney proximal cell line NRK-52E was treated with different concentrations (200, 400, and 800µmol/L) of it. Subsequently, three siRNAs targeting IGFBP7 were transfected with the HiPerFect reagent. The role of the JNK/ERK signaling pathway in uranium-induced kidney cytotoxicity was examined by a series of cell function experiments, including CCK-8 assay, TUNEL staining, RT-qPCR, Western blot, and flow cytometry analysis. Uranium inhibited NRK-52E cell viability and enhanced IGFBP7 expression in a dose-dependent manner. Silencing of IGFBP7 promoted cell cycle progression and inhibited cell apoptosis of uranium-treated cells. Mechanistically, silencing of IGFBP7 inhibited the uranium-activated JNK/ERK signaling pathway. The ERK1/2 signaling inhibitor PD98059 suppressed the IGFBP7-activated JNK/ERK signaling pathway. Furthermore, knockdown of IGFBP7 exerted a similar effect with PD98059 on uranium-induced NRK-52E cell cycle arrest and apoptosis. Silencing IGFBP7 inhibited the JNK/ERK signaling pathway to attenuate uranium-induced cytotoxicity and necrosis of NRK-52E cells.

The Association of Serum Biomarkers With Symptomatic Hemorrhagic Transformation in Acute Ischemic Stroke Patients: A Combined Retrospective and Prospective Study.

Symptomatic intracranial hemorrhage transformation (s-HT) is a serious complication of ischemic stroke, leading to early neurological deterioration and poor prognosis. It is an urgent problem to timely and effectively identify high-risk patients with s-HT at the early stage of stroke. However, so far, there are no effective clinical detection methods or measures. Therefore, the present study aimed to explore novel blood biomarkers related to s-HT. This study includes two parts: a retrospective study and a prospective cohort study. In the first part, s-HT patients were screened (n = 18), and non-s-HTs (n = 128) were selected from the same period of case patients in the retrospective study cohort. The baseline blood samples were obtained within 30 min of admission, and the levels of 92 proteins related to cerebrovascular diseases were detected using the Olink proteomics technology. Multivariate logistic regression and receiver operating characteristic curves were used to analyze the relationship between serum biomarker levels and s-HT. In the second part, s-HT patients (n = 28) and non-s-HTs (n = 130) were selected from a prospective study cohort, which met the same criteria for inclusion and exclusion. Enzyme-linked immunosorbent assay (ELISA) was used to measure the levels of potential biomarker(s) in serum screened from the first part to confirm its/their association(s) with s-HT. Olink assay showed that patients with s-HT had lower von Willebrand factor (vWF) levels and higher osteoprotegerin, phospholipase C, human insulin-like growth factor binding protein-7, matrix metalloproteinase-2, galectin-4, spondin-1 than non-s-HTs (n = 128) (p < 0.005) in a retrospective study cohort. Principal component (PC) and factor analysis showed that the seven biomarkers could explain 62.76% of the variance in the Olink biomarker set, and vWF was a main loading factor in PC2. Multivariate regression analysis showed that a low level of vWF was an independent risk factor (p < 0.05) for s-HT after adjusting for potential confounders. ELISA test results showed that s-HT patients had a significantly lower vWF levels than the non-s-HT group (26.57 [13.64-37.18] vs. 42.00 [26.02-55.52] ng/mL, p < 0.001) in the prospective study cohort. Incorporating vWF into the clinical risk factors significantly improved the accuracy of predicting s-HT (area under the curve [AUC, 0.731 vs. 0.641, p < 0.001], [AUC, 0.747 vs. 0.560, p < 0.001]) compared to a model employing only clinical risk factors in both study cohorts. Through the use of a combined retrospective and prospective study, vWF might be a novel blood biomarker for predicting s-HT occurrence in ischemic stroke patients.

The mechanism of high mobility group box-1 in the proliferation and macrophage polarization in esophageal squamous cell carcinoma cells

BackgroundPrevious studies showed that high mobility group box-1 (HMGB1) facilitates the initiation and progression of esophageal squamous cell carcinoma (ESCC), and the current research investigated the detailed mechanisms implicated.MethodsThe impact of HMGB1 and IGFBP3 levels on the survival of ESCC was examined by plotting Kaplan–Meier (KM) curves based on the data collected from The Cancer Genome Atlas (TCGA). Quantitative real-time PCR (qRT-PCR) was performed to detect the expressions of HMGB1 in both human esophageal epithelial cells (HEEC) and ESCC cells. After cell transfection, the proliferation of ESCC cells was measured, and the cell metastasis was determined based on the levels of cadherins (CDHs) and Vimentin (VIM). Macrophage polarization was determined by calculating the mean fluorescence intensity (MFI) of CD206 and CD86. In addition, co-immunoprecipitation and immunoblotting were applied to evaluate the interaction between insulin-like growth factor binding protein 3 (IGFBP3)/DNA-dependent protein kinase catalytic subunit (DNA–PKcs) and HMGB1.ResultsA high level of HMGB1 was predictive of an unfavorable prognosis of ESCC (p < 0.05). HMGB1 showed a higher expression in ESCC cells (p < 0.05), while knockdown of HMGB1 inhibited ESCC cell proliferation, downregulated the levels of CDH2 and VIM and upregulated the level of CDH1 (p < 0.05). In contrast, overexpressed HMGB1 showed the opposite effects (p < 0.05), suggesting the role of HMGB1 in the epithelial–mesenchymal transition (EMT) of ESCC. After the knockout of HMGB1, the MFI of CD86 was increased but that of CD206 was reduced, indicating the polarization towards M1 macrophages (p < 0.05). However, the results were reversed when HMGB1 was overexpressed (p < 0.05). Meanwhile, HMGB1 could interact with the IGFBP3/DNA–PKcs complex (p < 0.05). Low-expressed IGFBP3 was predictive of an unfavorable prognosis of ESCC, and IGFBP3 silencing promoted the proliferation of ESCC cells (p < 0.05). Besides, HMGB1 and IGFBP3 could act antagonistically in influencing the proliferation of ESCC cells and macrophage polarization.ConclusionsThrough in vitro experiments, this study found that HMGB1 was linked to the proliferation and polarization of macrophages in ESCC, providing novel evidence for the role of HMGB1 in ESCC development.

Antibodies against the receptor for insulin-like growth factor 1 (IGF-1RAb), insulin-like growth factor 1 (IGF-1), and insulin-like growth factor binding protein 3 (IGFBP-3) in the serum of patients with Graves' and Basedow's disease with and without orbitopathy.

Proven risk factors for thyroid orbitopathy (TO) are thyroid dysfunction, smoking, and high levels of thyrotropin receptor antibodies (TRAb), and the role of insulin-like growth factor 1 (IGF-1), the receptor for IGF-1 (IGF-1R), and antibodies to the receptor for IGF-1 (IGF-1RAb) are also debated. IGF-1R is overexpressed in fibroblasts and orbital lymphocytes in TO patients. It forms a functional complex and mediates signal transduction through thyroid stimulating hormone receptor (TSHR). The study aimed to evaluate the levels of IGF-1RAb, IGF-1, and IGFBP-3 in a group of Graves' and Basedow's disease (GBD) patients with or without TO. Sixty-seven patients were included in the study, including 47 GBD and 20 control patients. In the GBD group, 31 patients were diagnosed with active TO and were treated with immunosuppressive therapy according to the standard of European Group on Graves' Orbitopathy (EUGOGO) guidelines. In this group, 10 patients were in the sight-threatening stage of TO severity according to EUGOGO classification. IGF-1 and IGFBP-3 levels were determined with the use of chemiluminescence immunoassay (CLIA) methods. IGF-1RAb was measured by the "in-house" constructed enzyme-linked immunosorbent assay (ELISA) method. Including our cut-off value (Q75 - 232.48 ng/mL), positive serum IGF-1RAb was found in 25% of patients in the control group (5 out of 20 patients), in 38.3 % (18 out of 47 patients) of patients with GBD, and in 22.5% of GBD patients with active TO (7 out of 31 patients). In GBD patients with active TO, there were no differences in IGF-1RAb when compared to the control group but with a significantly lower level when compared to the GBD patients without active TO. The group of patients with active TO in the sight-threatening stage had significantly lower values of IGF-1RAb compared to the group of patients with GBD without the presence of TO (p = 0.004). There was also a difference in IGF-1RAb concentration between the groups in moderate-to-severe and sight-threatening stages of TO before starting immunosuppressive treatment (p = 0.014). There was no difference in IGF-1 levels between the control group and GBD patients with active TO before starting immunosuppressive treatment and GBD patients without active TO. The was a significant difference in IGF-1 concentration between the group with moderate-to-severe and sight-threatening stages of TO before starting immunosuppressive treatment (p = 0.009). We found significantly lower IGFBP-3 concentrations in GBD patients regardless of the presence of TO compared to the control group (p = 0.016). There was no difference in IGFBP-3 concentrations between patients with moderate-to-severe and sight-threatening stages of TO (p = 0.203). It seems that high IGF-1RAb levels may have a protective effect against the onset or severe course of TO, and patients with low IGF-1RAb levels are at risk for severe TO. Our results suggest that anti-receptor antibodies to IGF-1 are inhibitory antibodies.

Efficacy of Naringenin against aging and degeneration of nucleus pulposus cells through IGFBP3 inhibition

Naringenin (NAR), a natural flavonoid, exerts anti-inflammatory and antioxidant pharmacology. However, the pharmacological mechanisms through which NAR prevents and treats intervertebral disc degeneration (IDD) remain unclear. We utilized bioinformatics, machine learning, and network pharmacology to identify shared targets among NAR, senescence, and IDD. Subsequently, molecular docking was conducted to evaluate NAR’s binding affinity to common target. Additionally, we used IL-1β to induce senescence and degeneration in nucleus pulposus cells (NPCs) and conducted a series of cellular assays, including immunoblotting, immunofluorescence, β-galactosidase staining, cell proliferation, cell cycle analysis, and measurement of reactive oxygen species levels, to investigate NAR’s impact on IL-1β-induced senescence and degeneration of NPCs. Our study revealed that Insulin-like growth factor binding protein 3 (IGFBP3) was the only common target. IGFBP3 exhibited significant differences between the IDD and healthy groups and proved to be an effective diagnostic marker for IDD. Molecular docking confirmed the binding between NAR and IGFBP3. In vitro experiments, we observed that Igfbp3 expression increased in the senescence and degeneration groups. Igfbp3 knockdown and NAR attenuated IL-1β-induced senescence and degenerative phenotypes in NPCs. In contrast, the effect of NAR was attenuated by recombinant IGFBP3 protein. In conclusion, our findings suggest that NAR plays a preventive and therapeutic role in IDD, likely achieved through the inhibition of Igfbp3 expression.

Efficacy of urinary [TIMP-2]⋅[IGFBP7], L-FABP, and NGAL levels for predicting community-acquired acute kidney injury in Japanese patients: a single-center, prospective cohort study

BackgroundThe combination of urinary tissue inhibitor of metalloproteinase 2 (TIMP-2) and insulin-like growth factor-binding protein 7 (IGFBP7) ([TIMP-2]⋅[IGFBP7]) has emerged as a strong predictor of acute kidney injury (AKI), which is associated with poor outcomes. However, most studies have focused on non-Asian populations, and comparisons of [TIMP-2]⋅[IGFBP7] with other AKI biomarkers in Asian populations have not been performed. Furthermore, no study has examined the efficacy of [TIMP-2]⋅[IGFBP7] for predicting community-acquired AKI.MethodsWe prospectively enrolled adult patients at Kochi Medical School Hospital in Kochi, Japan, and performed a receiver-operating characteristic (ROC) curve analysis to assess the ability of [TIMP-2]⋅[IGFBP7], neutrophil gelatinase-associated lipocalin (NGAL), and liver fatty acid-binding protein (L-FABP) measured at the time of admission to predict AKI.ResultsOf the 170 enrolled patients, 40 (23.5%) developed AKI. Risk factors for AKI development were male sex, history of hypertension, low albumin levels, and high [TIMP-2]⋅[IGFBP7] and NGAL levels. The ROC curve analysis showed that the area under the ROC curve (AUC) of [TIMP-2]•[IGFBP7] for predicting AKI was 0.804 (95% confidence interval [CI], 0.728–0.880); however, the AUCs of L-FABP and NGAL were 0.688 (95% CI, 0.594–0.782) and 0.726 (95% CI, 0.639–0.813), respectively.ConclusionUrinary [TIMP-2]⋅[IGFBP7] is a good predictor of community-acquired AKI.

Expression and Methylation of Insulin-Like Growth Factor Binding Protein-1 Gene in Cord Blood of Intrauterine Growth Restricted Neonates.

To compare the insulin-like growth factor binding protein-1 (IGFBP-1) gene methylation and expression in the cord blood among intrauterine growth restricted (IUGR) and appropriate for gestational age (AGA) neonates and find their association with anthropometry at birth. Cord blood samples from IUGR and AGA neonates were collected. Anthropometric measurements i.e., Weight, length and head circumference of the infants were measured. RT-PCR was performed to examine IGFBP-1 gene expression and DNA methylation analysis by bisulfite sequencing PCR. The results were analyzed by using Mann-Whitney U test and Pearson correlation. IUGR neonates had significantly lower anthropometry (weight, length and head circumference) measurements at birth compared to AGA neonates. Gene expression analysis showed significantly higher IGFBP-1 gene expressions among IUGR compared to AGA neonates and gene expression level correlated with anthropometric measurements. There was no difference in IGFBP-1 gene methylation rate between the two groups of neonates and no correlation was observed with anthropometry. IGFBP-1 gene expression in cord blood was significantly higher among IUGR neonates and was associated with reduced birth weight, birth length and head circumference while the gene methylation was similar. This suggests involvement of multiple factors in occurrence of fetal growth restriction.