Insulin-like Growth Factor Binding Protein-3 Research Articles

Targeted proteomic profiling of cardiogenic shock in the cardiac intensive care unit.

We sought to characterize circulating protein biomarkers associated with cardiogenic shock (CS) using highly multiplex proteomic profiling. This analysis employed a cross-sectional case-control study design using a biorepository of patients admitted to a cardiac intensive care unit between 2017 and 2020. Cases were patients adjudicated to have CS, and controls were those presenting for cardiac critical care without shock, including subsets of patients with isolated hypotension or heart failure (HF). The Olink platform was used to analyse 359 biomarkers with Bonferroni correction. The analysis included 239 patients presenting for cardiac critical care (69 cases with CS, 170 non-shock controls). A total of 63 biomarkers (17.7%) were significantly associated with CS after Bonferroni correction compared with all controls. Of these, nine biomarkers remained significantly associated with CS when separately cross-validated in subsets of controls presenting with isolated hypotension and HF: cathepsin D, fibroblast growth factor (FGF)-21 and -23, growth differentiation factor (GDF)-15, insulin-like growth factor-binding protein-1, N-terminal pro-B-type natriuretic peptide, osteopontin, oncostatin-M-specific receptor subunit beta (OSMR), and soluble ST2 protein (sST2). Four biomarkers were identified as providing complementary information for CS diagnosis with development of a multi-marker model: sST2, FGF-23, CTSD, and GDF-15. In this pilot study of targeted proteomic profiling in CS, we identified nine biomarkers significantly associated with CS when cross-validated against non-shock controls including those with HF or isolated hypotension, illustrating the potential application of a targeted proteomic approach to identify novel candidates that may support the diagnosis of CS.

Plasma proteome association with coronary heart disease and carotid intima media thickness: results from the KORA F4 study

Background and aimsAtherosclerosis is the main cause of stroke and coronary heart disease (CHD), both leading mortality causes worldwide. Proteomics, as a high-throughput method, could provide helpful insights into the pathological mechanisms underlying atherosclerosis. In this study, we characterized the associations of plasma protein levels with CHD and with carotid intima-media thickness (CIMT), as a surrogate measure of atherosclerosis.MethodsThe discovery phase included 1000 participants from the KORA F4 study, whose plasma protein levels were quantified using the aptamer-based SOMAscan proteomics platform. We evaluated the associations of plasma protein levels with CHD using logistic regression, and with CIMT using linear regression. For both outcomes we applied two models: an age-sex adjusted model, and a model additionally adjusted for body mass index, smoking status, physical activity, diabetes status, hypertension status, low density lipoprotein, high density lipoprotein, and triglyceride levels (fully-adjusted model). The replication phase included a matched case-control sample from the independent KORA F3 study, using ELISA-based measurements of galectin-4. Pathway analysis was performed with nominally associated proteins (p-value < 0.05) from the fully-adjusted model.ResultsIn the KORA F4 sample, after Bonferroni correction, we found CHD to be associated with five proteins using the age-sex adjusted model: galectin-4 (LGALS4), renin (REN), cathepsin H (CTSH), and coagulation factors X and Xa (F10). The fully-adjusted model yielded only the positive association of galectin-4 (OR = 1.58, 95% CI = 1.30–1.93), which was successfully replicated in the KORA F3 sample (OR = 1.40, 95% CI = 1.09–1.88). For CIMT, we found four proteins to be associated using the age-sex adjusted model namely: cytoplasmic protein NCK1 (NCK1), insulin-like growth factor-binding protein 2 (IGFBP2), growth hormone receptor (GHR), and GDNF family receptor alpha-1 (GFRA1). After assessing the fully-adjusted model, only NCK1 remained significant (β = 0.017, p-value = 1.39e-06). Upstream regulators of galectin-4 and NCK1 identified from pathway analysis were predicted to be involved in inflammation pathways.ConclusionsOur proteome-wide association study identified galectin-4 to be associated with CHD and NCK1 to be associated with CIMT. Inflammatory pathways underlying the identified associations highlight the importance of inflammation in the development and progression of CHD.

Exosomal Serum Biomarkers as Predictors for Laryngeal Carcinoma.

The lack of screening methods for LSCC is a critical issue, as treatment options and the treatment outcome greatly depend on the stage of LSCC at initial diagnosis. Therefore, the objective of this study was to identify potential exosomal serum biomarkers that can diagnose LSCC and distinguish between early- and late-stage disease. A multiplexed proteomic array was used to identify differentially expressed proteins in exosomes isolated from the serum samples of LSCC patients compared to the control group (septorhinoplasty, SRP). The most promising proteins for diagnosis and differentiation were calculated using biostatistical methods and were validated by immunohistochemistry (IHC), Western blots (WB), and ELISA. Exosomal insulin-like growth factor binding protein 7 (IGFBP7) and Annexin A1 (ANXA1) were the most promising exosomal biomarkers for distinguishing between control and LSCC patients and also between different stages of LSCC (fold change up to 15.9, p < 0.001 for all). The identified proteins represent potentially novel non-invasive biomarkers. However, these results need to be validated in larger cohorts with a long-term follow-up. Exosomal biomarkers show a superior signal-to-noise ratio compared to whole serum and may therefore be an important tool for non-invasive biomarker profiling for laryngeal carcinoma in the future.

IGFBP2 induces podocyte apoptosis promoted by mitochondrial damage via integrin α5/FAK in diabetic kidney disease.

Podocyte apoptosis or loss is the pivotal pathological characteristic of diabetic kidney disease (DKD). Insulin-like growth factor-binding protein 2 (IGFBP2) have a proinflammatory and proapoptotic effect on diseases. Previous studies have shown that serum IGFBP2 level significantly increased in DKD patients, but the precise mechanisms remain unclear. Here, we found that IGFBP2 levels obviously increased under a diabetic state and high glucose stimuli. Deficiency of IGFBP2 attenuated the urine protein, renal pathological injury and glomeruli hypertrophy of DKD mice induced by STZ, and knockdown or deletion of IGFBP2 alleviated podocytes apoptosis induced by high concentration of glucose or in DKD mouse. Furthermore, IGFBP2 facilitated apoptosis, which was characterized by increase in inflammation and oxidative stress, by binding with integrin α5 (ITGA5) of podocytes, and then activating the phosphorylation of focal adhesion kinase (FAK)-mediated mitochondrial injury, including membrane potential decreasing, ROS production increasing. Moreover, ITGA5 knockdown or FAK inhibition attenuated the podocyte apoptosis caused by high glucose or IGFBP2 overexpression. Taken together, these findings unveiled the insight mechanism that IGFBP2 increased podocyte apoptosis by mitochondrial injury via ITGA5/FAK phosphorylation pathway in DKD progression, and provided the potential therapeutic strategies for diabetic kidney disease.

Mechanism and clinical role of TIMP-2 and IGFBP-7 in cardiac surgery-associated acute kidney injury: A review.

Acute kidney injury (AKI) is a common postoperative complication, but there is still a lack of accurate biomarkers. Cardiac surgery-associated AKI is the most common cause of major-surgery-related AKI, and patients requiring renal replacement therapy have high mortality rates. Early diagnosis, intervention, and management are crucial for improving patient prognosis. However, diagnosing AKI based solely on changes in serum creatinine level and urine output is insufficient, as these changes often lag behind actual kidney damage, making early detection challenging. Biomarkers such as tissue inhibitor of metalloproteinases-2 (TIMP-2) and insulin-like growth factor-binding protein-7 (IGFBP-7) have been found to be significant predictors of moderate-to-severe AKI when combined with urine content analysis. This article reviews the mechanism of biomarkers TIMP-2 and IGFBP-7 in AKI and provides a comprehensive overview of the clinical effects of TIMP-2 and IGFBP-7 in cardiac surgery-associated AKI, including prediction, diagnosis, and progression.

Clinical determinants of blood biomarkers of atrial cardiomyopathy: results from the ISOLATION AF ablation cohort study

Abstract Background In patients with atrial fibrillation (AF), significant advances have been made in identifying biomarkers representing diverse pathophysiological pathways, such as inflammation, myocyte injury, collagen deposition, and fatty-fibrotic infiltration. Data on clinical determinants of biomarkers in patients with AF, however, are lacking. Objective Our primary aim was to explore the relationships between clinical determinants and biomarker levels in AF patients scheduled for catheter ablation. Methods A cross-sectional analysis was conducted in AF patients undergoing catheter ablation included in the prospective multicenter ISOLATION study between July 2020 and May 2022. Clinical characteristics, routine tests and blood samples were collected before ablation. Blood samples were analyzed for known and novel cardiovascular biomarkers, including Bone morphogenetic protein 10 (BMP10), Angiopoietin-2 (Ang-2), Fibroblast growth factor 23 (FGF-23), Dickkopf-related protein 3 (DKK-3), Endocan (ESM-1), Insulin-like growth factor-binding protein 7 (IGFBP-7), B-type natriuretic peptides (proBNP, NTproBNP), High sensitive Troponin-T (hsTnT)&amp;lt; Growth differentiation factor 15 (GDF-15), interleukin 6 (IL-6), Fatty acid binding protein 3 (FABP3), Cancer antigen-125 (Ca-125) (Table 1). For each biomarker we trained a lasso regression model to identify the most important clinical determinants out of all the 60 available determinants (including anthropometry, ECG, comorbidities). The strongest associations are summarized in figure 1. Results Blood samples of 508 patients were analyzed. The mean age was 63 ±9 years, and 31.1% were female. 354 patients (69.7%) had paroxysmal AF and 154 patients (30.3%) had persistent AF. Heart failure was reported in 77 patients (15.2%). 355 (72.3%) patients were in sinus rhythm during sample collection. The following clinical determinants of biomarker levels were frequently identified as important: rhythm during blood phlebotomy, age, heart failure, decreased kidney function and female sex (Figure 1). Most notably, rhythm at the time of sampling was strongly associated with various biomarker levels. Female sex was positively associated with BMP10 and FGF23 (atrial fibrosis), but negatively associated with hsTNT (cardiac injury). Conclusion In patients with AF scheduled for catheter ablation, we identified several clinical determinants of biomarker levels with potential implications for disease mechanisms. In women, pro-fibrotic biomarkers were frequently higher, while male patients more often showed signs of myocardial injury. Importantly, rhythm during blood draw is a very strong determinant of many biomarkers and should be taken into account in future biomarker studies.Figure 1.Table 1.

#1211 IGFBP-5/TGF-β1-mediated cell crosstalk between endothelia and tubular epithelia promotes renal fibrosis

Abstract Background and Aims Renal fibrosis is a common pathophysiological characteristic of chronic kidney disease (CKD) for which there is no effective treatment. The mechanism of renal fibrosis is complicated and remains unclear. Our previous study revealed that Insulin-like growth factor binding protein 5 (IGFBP-5) induces glycolytic activation in ECs and ultimately aggravates renal inflammation in diabetic kidney disease (DKD). This study aims to discover the relationship between IGFBP-5 and renal fibrosis. Method HK-2 and HUVEC cells were included in this study. UUO and ANN model were obstructed by Wild-type, IGFBP-5−/− and IGFBP-5flox/flox, cre mice. IGFBP-5, TGF-β and fibrosis makers were detected to explore the mechanism of IGFBP-5 in fibrosis. Results We found that the serum IGFBP-5 levels were significantly increased in CKD, that IGFBP-5 was dominantly localized in vascular endothelial cells (ECs) of kidney tissue, and that IGFBP-5 deficiency relieved renal fibrosis in CKD model mice. In vitro experiments indicated that IGFBP-5 exacerbated the fibrosis phenotypic alteration of tubular epithelial cells (TECs) by the TGF-β1/p-Smad3 signaling pathway. In turn, TGF-β1 could facilitate the synthesis of IGFBP-5 in ECs. The crosstalk between TECs and ECs mediated by IGFBP-5 and TGF-β1 was confirmed in a coculture system and endothelial-specific IGFBP-5-deficient mice. Conclusion Renal fibrosis is exacerbated by TEC-EC cellular crosstalk through the feedback loop consisting of IGFBP-5 and TGF-β1. These findings suggest that IGFBP-5 may be a new pathogenic factor in renal fibrosis and a potential new therapeutic target in CKD.

Biological Variation Data in Triathletes for Metabolism and Growth-Related Biomarkers Included in the Athlete Biological Passport.

When using biological variation (BV) data, BV estimates need to be robust and representative. High-endurance athletes represent a population under special physiological conditions, which could influence BV estimates. Our study aimed to estimate BV in athletes for metabolism and growth-related biomarkers involved in the Athlete Biological Passport (ABP), by 2 different statistical models. Thirty triathletes were sampled monthly for 11 months. The samples were analyzed for human growth hormone (hGH), insulin-like growth factor-1 (IGF-1), insulin-like growth factor binding protein 3 (IGFBP-3), insulin, and N-terminal propeptide of type III procollagen (P-III-NP) by immunoassay. Bayesian and ANOVA methods were applied to estimate within-subject (CVI) and between-subject BV. CVI estimates ranged from 7.8% for IGFBP-3 to 27.0% for insulin, when derived by the Bayesian method. The 2 models gave similar results, except for P-III-NP. Data were heterogeneously distributed for P-III-NP for the overall population and in females for IGF-1 and IGFBP-3. BV components were not estimated for hGH due to lack of steady state. The index of individuality was below 0.6 for all measurands, except for insulin. In an athlete population, to apply a common CVI for insulin would be appropriate, but for IGF-1 and IGFBP-3 gender-specific estimates should be applied. P-III-NP data were heterogeneously distributed and using a mean CVI may not be representative for the population. The high degree of individuality for IGF-1, IGFBP-3, and P-III-NP makes them good candidates to be interpreted through reference change values and the ABP.

#2508 Urinary [TIMP-2]*[IGFBP7] as the ultimate potential biomarker of subclinical Acute Kidney Injury after kidney surgery: a multicentric study

Abstract Background and Aims Nephron-sparing surgery (NSS) represents the preferred technique to treat localized renal lesions and better preserve kidney function. Still it is not exempted from the risk of postoperative acute kidney injury (AKI) to happen, with a reported incidence ranging from 5.5% to 34%. Patients experiencing postoperative AKI, either clinical or subclinical, are more susceptible to chronic kidney disease (CKD). The latter represents a difficult-to-identify subpopulation characterized by tubular damage biomarker's rising without changes in serum creatinine (scr), that after surgery is less likely to be included among the ones deserving a closer follow-up, but actually needing one, as this subpopulation's long term outcomes slightly differ from individuals recovered from clinical postoperative AKI. This is the reason why a standardized tool for early identification of patients suffering from subclinical AKI is required, to allow a customized postoperative surveillance, promote strategies of nephroprotection and reduce the incidence of CKD and end-stage kidney disease. Recent evidences show that by exclusively following outdated consensus criteria for AKI (changes in scr, urine output), 15-20% of patients undergoing through acute tubular injury and suffering from its adverse outcomes are likely to be missed. Only recently, FDA approved NephroCheck® biomarker, which combines two urinary markers, tissue inhibitor of metalloproteinases-2 (TIMP-2) and insulin-like growth factor-binding protein 7 (IGFBP7). It represents the first effective test for AKI's risk assessment. In a previous monocentric study [1], our group presented NephroCheck® as a biomarker able to efficiently identify subclinical AKI and predict long-term eGFR decline after robotic NSS. In order to confirm our previous results, we recruited a larger cohort and performed a multicentric study. Method We prospectively observed all patients scheduled for robotic NSS in suspected localized renal cell carcinoma in two different Centers from 2016 to 2018. Samples were collected preoperatively and postoperatively (4 h, 10 h, 24 h, 48 h), while kidney function was re-assessed up to 24 months. A multivariate logistic analysis was performed to evaluate the association between different parameters and eGFR decline at 24 months. Results A total number of 131 patients were included; 55/131 (42%) developed clinical AKI. A significant association between NephroCheck® at 4 h and clinical AKI, as stated by KDIGO Guidelines, is confirmed (p = 0.0055). In the overall cohort, the multivariate analysis shows that only clinical AKI appears as an independent factor for predicting eGFR decline at 24 months (p &amp;lt; 0.0003), while postoperative NephroCheck® alone did not (p = 0.92). Based on NephroCheck® measured 4 h after surgery and clinical AKI, patients can be divided in four groups with significantly different eGFR at 24 months (p = 0.0003) (Fig. 1). Not considering patients who experienced clinical AKI, the independent role of different parameters in predicting severe eGFR decline at 24 months was evaluated by multivariate logistic analysis; in this subgroup of patients, NephroCheck® evaluated at 4 h postoperatively appears as an independent factor able to predict a severe eGFR decline at 24 months (OR 3.76, p = 0.02) (Fig. 2). Conclusion NephroCheck®, in combination with scr, represents an accurate and easy-to-use test, likely able to early identify long-term eGFR decline in patients undergoing NSS surgery that don't develop a clinically evident postoperative AKI (subclinical AKI), making it possible to identify those in need of closer-up surveillance, reducing the incidence and progression of CKD. Still, clinical postoperative AKI is confirmed as the most important prognostic parameter and predictive factor for eGFR decline in the long-term. Further studies are needed, particularly focusing on application of NephroCheck® in setting other than NSS.

Decreased thrombospondin-1 impairs endometrial stromal decidualization in unexplained recurrent spontaneous abortion†.

Inappropriate endometrial stromal decidualization has been implied as an important reason of many pregnancy-related complications, such as unexplained recurrent spontaneous abortion, preeclampsia, and intrauterine growth restriction. Here, we observed that thrombospondin-1, an adhesive glycoprotein, was significantly downregulated in endometrial decidual cells from patients with unexplained recurrent spontaneous abortion. The immortalized human endometrial stromal cell line was used to investigate the possible THBS1-mediated regulation of decidualization. In vitro experiments found that the expression level of THBS1 increased with the normal decidualization process. Knockdown of THBS1 could decrease the expression levels of prolactin and insulin-like growth factor binding protein-1, two acknowledged human decidualization markers, whereas THBS1 overexpression could reverse these effects. The RNA sequencing results demonstrated that the extracellular regulated protein kinases signaling pathway was potentially affected by the knockdown of THBS1. We further confirmed that the regulation of THBS1 on decidualization was achieved through the ERK signaling pathway by the treatment of inhibitors. Moreover, knockdown of THBS1 in pregnant mice could impair decidualization and result in an increased fetus resorption rate. Altogether, our study demonstrated a crucial role of THBS1 in the pathophysiological process of unexplained recurrent spontaneous abortion and provided some new insights into the research of pregnancy-related complications.

Deciphering smooth muscle cell heterogeneity in atherosclerotic plaques and constructing model: a multi-omics approach with focus on KLF15/IGFBP4 axis

BackgroundRuptured atherosclerotic plaques often precipitate severe ischemic events, such as stroke and myocardial infarction. Unraveling the intricate molecular mechanisms governing vascular smooth muscle cell (VSMC) behavior in plaque stabilization remains a formidable challenge.MethodsIn this study, we leveraged single-cell and transcriptomic datasets from atherosclerotic plaques retrieved from the gene expression omnibus (GEO) database. Employing a combination of single-cell population differential analysis, weighted gene co-expression network analysis (WGCNA), and transcriptome differential analysis techniques, we identified specific genes steering the transformation of VSMCs in atherosclerotic plaques. Diagnostic models were developed and validated through gene intersection, utilizing the least absolute shrinkage and selection operator (LASSO) and random forest (RF) methods. Nomograms for plaque assessment were constructed. Tissue localization and expression validation were performed on specimens from animal models, utilizing immunofluorescence co-localization, western blot, and reverse-transcription quantitative-polymerase chain reaction (RT-qPCR). Various online databases were harnessed to predict transcription factors (TFs) and their interacting compounds, with determination of the cell-specific localization of TF expression using single-cell data.ResultsFollowing rigorous quality control procedures, we obtained a total of 40,953 cells, with 6,261 representing VSMCs. The VSMC population was subsequently clustered into 5 distinct subpopulations. Analyzing inter-subpopulation cellular communication, we focused on the SMC2 and SMC5 subpopulations. Single-cell subpopulation and WGCNA analyses revealed significant module enrichments, notably in collagen-containing extracellular matrix and cell-substrate junctions. Insulin-like growth factor binding protein 4 (IGFBP4), apolipoprotein E (APOE), and cathepsin C (CTSC) were identified as potential diagnostic markers for early and advanced plaques. Notably, gene expression pattern analysis suggested that IGFBP4 might serve as a protective gene, a hypothesis validated through tissue localization and expression analysis. Finally, we predicted TFs capable of binding to IGFBP4, with Krüppel-like family 15 (KLF15) emerging as a prominent candidate showing relative specificity within smooth muscle cells. Predictions about compounds associated with affecting KLF15 expression were also made.ConclusionOur study established a plaque diagnostic and assessment model and analyzed the molecular interaction mechanisms of smooth muscle cells within plaques. Further analysis revealed that the transcription factor KLF15 may regulate the biological behaviors of smooth muscle cells through the KLF15/IGFBP4 axis, thereby influencing the stability of advanced plaques via modulation of the PI3K-AKT signaling pathway. This could potentially serve as a target for plaque stability assessment and therapy, thus driving advancements in the management and treatment of atherosclerotic plaques.

Lysosome dynamics during human endometrial stromal cells decidualization: effect of para-nonylphenol.

During the process of decidualization, the stromal cells of the endometrium change dynamically to create a favorable environment for embryo implantation. Lysosome activity has often been associated with physiological changes in the endometrium during the pre-implantation period and early pregnancy. In this study, the effect of para-nonylphenol (p-NP), an endocrine disruptor, on human immortalized endometrial stromal cells (tHESCs) was investigated. After exposure to p-NP (1 nM and 1 pM), the cells were examined for the decidualization markers Connexin-43, insulin like growth factor binding protein 1 (IGFBP1) and Prolactin. In addition, the effect of p-NP on lysosome biogenesis and exocytosis was investigated by examining the expression and localization of the transcription factor EB (TFEB) and that of the lysosomal-associated membrane protein 1 (LAMP-1). Finally, we evaluated the effect of p-NP on ECM remodeling using a fibronectin assay. Our results showed that p-NP reduced the expression of Prolactin protein, increased the nuclear localization of TFEB, and induced the increase and translocation of the lysosomal protein LAMP-1 to the membrane of tHESCs. The data indicate an impairment of decidualization and suggest an increase in lysosomal biogenesis and exocytosis, which is supported by the higher release of active cathepsin D by tHESCs. Given the importance of cathepsins in the processing and degradation of the ECM during trophoblast invasiveness and migration into the decidua, our results appear to be clear evidence of the negative effects of p-NP on endometrial processes that are fundamental to reproductive success and the establishment of pregnancy.

Comparison of the efficacy of 0.9% normal saline with balanced crystalloid (Plasmalyte) in maintaining the metabolic profile in head injury patients undergoing evacuation of acute subdural haematoma - A randomised controlled trial.

The choice of intravenous fluids is important in patients with traumatic brain injury (TBI), where large volumes may be required for resuscitation. Our study aimed to compare 0.9% normal saline (NS) with balanced crystalloid (Plasmalyte) in TBI patients in terms of metabolic and coagulation profile, brain relaxation score (BRS) and renal functions using serum urea, creatinine and urinary tissue inhibitor of metalloproteinases-2* insulin-like growth factor binding protein-7, [TIMP-2]*[IGFBP7], value to assess the risk of acute kidney injury. This randomised controlled trial on 90 TBI patients undergoing emergency craniotomy and subdural haematoma evacuation was conducted in a tertiary care institute. The patients were randomised to receive either NS (Group NS) or Plasmalyte (Group P) as the intraoperative maintenance fluid. The primary outcome measures included the potential of hydrogen (pH), base excess (BE) and chloride values from an arterial blood gas. The secondary outcomes were the coagulation profile, BRS and urinary [TIMP-2]*[IGFBP7]. The two groups' metabolic profile differences were analysed using two-way repeated analysis of variance. BRS was analysed using the Mann-Whitney U test. A P value < 0.05 was considered to be statistically significant. The pH and chloride values were significantly higher, and the BE values were significantly lower in Group P compared to Group NS (P < 0.001). Brain relaxation and coagulation profiles were comparable between the two groups. Serum creatinine (P = 0.002) and urinary [TIMP-2]*[IGFBP7] (P = 0.042) were significantly higher in the NS group. Plasmalyte maintains a more favourable metabolic profile than NS in TBI patients without affecting brain relaxation adversely.

Quantitative ultrasound techniques and biochemical markers to assess liver steatosis and fibrosis in newly diagnosed acromegaly

PurposeThe liver is known to be protected from steatosis under the influence of high GH/IGF-1. Cytokeratin 18 (CK18) and insulin-like growth factor binding protein 7 (IGFBP7) increase in liver steatosis and fibrosis. The aim of this study was to use quantitative ultrasound techniques and biochemical markers to assess liver steatosis and liver fibrosis in newly diagnosed acromegaly.MethodsThis single-center, cross-sectional study included 23 patients with newly diagnosed acromegaly and 46 age, sex, body mass index (BMI) and waist circumference (WC)-matched controls. Liver steatosis was assessed using tissue attenuation imaging (TAI), and stiffness, indicative of fibrosis, was assessed by shear wave elastography (SWE). Serum IGFBP7 and CK18 were studied by ELISA.ResultsThe acromegaly group had significantly lower liver steatosis (p = 0.006) and higher liver stiffness (p = 0.004), serum IGFBP7 (p = 0.048) and CK18 (p = 0.005) levels than the control group. The presence of fibrosis (p = 0.012) was significantly higher in the acromegaly group than in the control group. Moreover, CK18 was positively correlated with liver stiffness, WC, HOMA-IR, HbA1c, and triglyceride. In the acromegaly group, liver steatosis was negatively correlated with GH level. Stepwise multiple linear regression analysis revealed that BMI (p = 0.008) and CK18 (p = 0.015) were independent risk factors for increased liver stiffness.ConclusionThis study showed that there was an increased presence of liver fibrosis independent of liver steatosis in newly diagnosed acromegaly. Serum CK18 appears to be a potential marker of increased liver fibrosis in acromegaly.

A Nonlinear Relation between Body Mass Index and Long-Term Poststroke Functional Outcome-The Importance of Insulin Resistance, Inflammation, and Insulin-like Growth Factor-Binding Protein-1.

Both high serum insulin-like growth factor-binding protein-1 (s-IGFBP-1) and insulin resistance (IR) are associated with poor functional outcome poststroke, whereas overweight body mass index (BMI; 25-30) is related to fewer deaths and favorable functional outcome in a phenomenon labeled "the obesity paradox". Furthermore, IGFBP-1 is inversely related to BMI, in contrast to the linear relation between IR and BMI. Here, we investigated s-IGFBP-1 and IR concerning BMI and 7-year poststroke functional outcome. We included 451 stroke patients from the Sahlgrenska Study on Ischemic Stroke (SAHLSIS) with baseline measurements of s-IGFBP1, homeostasis model assessment of IR (HOMA-IR), BMI (categories: normal-weight (8.5-25), overweight (25-30), and obesity (>30)), and high-sensitivity C-reactive protein (hs-CRP) as a measure of general inflammation. Associations with poor functional outcome (modified Rankin scale [mRS] score: 3-6) after 7 years were evaluated using multivariable binary logistic regression, with overweight as reference due to the nonlinear relationship. Both normal-weight (odds-ratio [OR] 2.32, 95% confidence interval [CI] 1.30-4.14) and obese (OR 2.25, 95% CI 1.08-4.71) patients had an increased risk of poor functional outcome, driven by deaths only in the normal-weight. In normal-weight, s-IGFBP-1 modestly attenuated (8.3%) this association. In the obese, the association was instead attenuated by HOMA-IR (22.4%) and hs-CRP (10.4%). Thus, a nonlinear relation between BMI and poor 7-year functional outcome was differently attenuated in the normal-weight and the obese.

Plasma IGFBP-3 and IGFBP-5 levels are decreased during acute manic episodes in bipolar disorder patients.

Introduction: Bipolar disorder (BD) is a recurrent and disabling psychiatric disorder related to low-grade peripheral inflammation and altered levels of the members of the insulin-like growth factor (IGF) family. The aim of this study was to evaluate the plasma levels of IGF-2, insulin-like growth factor-binding protein 1 (IGFBP-1), IGFBP-3, IGFBP-5, IGFBP-7, and inflammatory markers such as tumor necrosis factor α (TNF-α), monocyte chemoattractant protein 1 (MCP-1), and macrophage inflammatory protein 1β (MIP-1β). Methods: We used the Young Mania Rating Scale (YMRS) to determine the severity of the symptomatology, while proteins were measured by enzyme-linked immunosorbent assay (ELISA). We included 20 patients with BD who suffered a manic episode and 20 controls. Some BD patients (n = 10) were evaluated after a period (17 ± 8days) of pharmacological treatment. Results: No statistical difference was found in IGF-2, IGFBP-1, IGFBP-7, TNF-α, and MIP-1β levels. However, IGFBP-3 and IGFBP-5 levels were found to be statistically decreased in BD patients. Conversely, the MCP-1 level was significantly increased in BD patients, but their levels were normalized after treatment. Intriguingly, only IGFBP-1 levels were significantly decreased after treatment. No significant correlation was found between the YMRS and any of the proteins studied either before or after treatment or between IGF proteins and inflammatory markers. Discussion: To some extent, IGFBP-3 and IGFBP-5 might be further explored as potential indicators of treatment responsiveness or diagnosis biomarkers in BD.

Key mRNAs and lncRNAs of pituitary that affect the reproduction of FecB + + small tail han sheep

BackgroundThe pituitary directly regulates the reproductive process through follicle-stimulating hormone (FSH) and luteinizing hormone (LH). Transcriptomic research on the pituitaries of ewes with different FecB (fecundity Booroola) genotypes has shown that some key genes and lncRNAs play an important role in pituitary function and sheep fecundity. Our previous study found that ewes with FecB + + genotypes (without FecB mutation) still had individuals with more than one offspring per birth. It is hoped to analyze this phenomenon from the perspective of the pituitary transcriptome.ResultsThe 12 Small Tail Han Sheep were equally divided into polytocous sheep in the follicular phase (PF), polytocous sheep in the luteal phase (PL), monotocous sheep in the follicular phase (MF), and monotocous sheep in the luteal phase (ML). Pituitary tissues were collected after estrus synchronous treatment for transcriptomic analysis. A total of 384 differentially expressed genes (DEGs) (182 in PF vs. MF and 202 in PL vs. ML) and 844 differentially expressed lncRNAs (DELs) (427 in PF vs. MF and 417 in PL vs. ML) were obtained from the polytocous-monotocous comparison groups in the two phases. Functional enrichment analysis showed that the DEGs in the two phases were enriched in signaling pathways known to play an important role in sheep fecundity, such as calcium ion binding and cAMP signaling pathways. A total of 1322 target relationship pairs (551 pairs in PF vs. MF and 771 pairs in PL vs. ML) were obtained for the target genes prediction of DELs, of which 29 DEL-DEG target relationship pairs (nine pairs in PF vs. MF and twenty pairs in PL vs. ML). In addition, the competing endogenous RNA (ceRNA) networks were constructed to explore the regulatory relationships of DEGs, and some important regulatory relationship pairs were obtained.ConclusionAccording to the analysis results, we hypothesized that the pituitary first receives steroid hormone signals from the ovary and uterus and that VAV3 (Vav Guanine Nucleotide Exchange Factor 3), GABRG1 (Gamma-Aminobutyric Acid A Receptor, Gamma 1), and FNDC1 (Fibronectin Type III Domain Containing 1) played an important role in this process. Subsequently, the reproductive process was regulated by gonadotropins, and IGFBP1 (Insulin-like Growth Factor Binding Protein 1) was directly involved in this process, ultimately affecting litter size. In addition, TGIF1 (Transforming Growth Factor-Beta-Induced Factor 1) and TMEFF2 (Transmembrane Protein With EGF Like And Two Follistatin Like Domains 2) compensated for the effect of the FecB mutation and function by acting on TGF-β/SMAD signaling pathway, an important pathway for sheep reproduction. These results provided a reference for understanding the mechanism of multiple births in Small Tail Han Sheep without FecB mutation.

The Importance of Lung Ultrasound and IGFBP7 (Insulin-like Growth Factor Binding Protein 7) Assessment in Diagnosing Patients with Heart Failure.

Background: In daily practice, there are problems with adequately diagnosing the cause of dyspnea in patients with heart failure with preserved and mildly reduced ejection fractions (HFpEF and HFmrEF). This study aimed to assess the usefulness of lung ultrasound in diagnosing HFpEF and HFmrEF and determine its correlation with IGFBP7 (insulin-like growth factor binding protein 7), NTproBNP (N-terminal pro-B-type natriuretic peptide), and echocardiographic markers. Methods: The research was conducted on 143 patients hospitalized between 2018 and 2020, admitted due to dyspnea, and diagnosed with HFpEF and HFmrEF. Venous blood was collected from all participants to obtain basic biochemical parameters, NTproBNP, and IGFBP7. Moreover, all participants underwent echocardiography and transthoracic lung ultrasound. Two years after hospitalization a follow-up telephone visit was performed. Results: The number of B-lines in the LUS ≥ 16 was determined with a sensitivity of-73% and specificity of-62%, indicating exacerbation of heart failure symptoms on admission. The number of B-lines ≥ 14 on admission was determined as a cut-off point, indicating an increased risk of death during the 2-year follow-up period. The factors that significantly impacted mortality in the study patient population were age and the difference between the number of B-lines on ultrasound at admission and at hospital discharge. IGFBP7 levels had no significant effect on the duration of hospitalization, risk of rehospitalization, or mortality during follow-up. Conclusions: Lung ultrasonography provides additional diagnostic value in patients with HFpEF or HFmrEF and exacerbation of heart failure symptoms. The number of B-lines ≥ 14 may indicate an increased risk of death.

Single cell lineage tracing reveals clonal dynamics of anti-EGFR therapy resistance in triple negative breast cancer

BackgroundMost primary Triple Negative Breast Cancers (TNBCs) show amplification of the Epidermal Growth Factor Receptor (EGFR) gene, leading to increased protein expression. However, unlike other EGFR-driven cancers, targeting this receptor in TNBC yields inconsistent therapeutic responses.MethodsTo elucidate the underlying mechanisms of this variability, we employ cellular barcoding and single-cell transcriptomics to reconstruct the subclonal dynamics of EGFR-amplified TNBC cells in response to afatinib, a tyrosine kinase inhibitor (TKI) that irreversibly inhibits EGFR.ResultsIntegrated lineage tracing analysis revealed a rare pre-existing subpopulation of cells with distinct biological signature, including elevated expression levels of Insulin-Like Growth Factor Binding Protein 2 (IGFBP2). We show that IGFBP2 overexpression is sufficient to render TNBC cells tolerant to afatinib treatment by activating the compensatory insulin-like growth factor I receptor (IGF1-R) signalling pathway. Finally, based on reconstructed mechanisms of resistance, we employ deep learning techniques to predict the afatinib sensitivity of TNBC cells. ConclusionsOur strategy proved effective in reconstructing the complex signalling network driving EGFR-targeted therapy resistance, offering new insights for the development of individualized treatment strategies in TNBC.

Yak IGFBP3 promotes hepatocyte proliferation through PI3K-Akt signaling pathway

IGFBP3 (Insulin-like growth factor binding protein 3) constitutes a crucial constituent of the insulin-like growth factor (IGF), which are intimately associated with the organism's growth and development processes. Despite its significance, the precise function of IGFBP3 in yak liver development remains largely unexplored. In the present study, we systematically examined the expression profile of IGFBP3 in the liver tissues of yaks across various growth stages, elucidated its influence on the activity of yak hepatocytes, and probed its effects on murine liver development. A comparative analysis revealed that the expression of IGFBP3 was significantly higher in the liver tissue of 5-year-old yaks compared to their 15-month-old and 1-day-old counterparts (P < 0.01). To further validate its biological function, pET-28a-BgIGFBP3 prokaryotic expression vector was constructed. Upon exposing yak hepatocytes to varying concentrations of Bos grunniens (Bg) IGFBP3 protein, we observed augmented cellular activities and elevated colony formation rates. Moreover, our investigation revealed the upregulation of key genes within the PI3K-Akt signaling pathway, including ERBB2, IRS1, PIK3R1, AKT1, RAF1, MAP2K2, and MAPK3, in both yak hepatocyte cultures and murine models. These findings collectively indicate that BgIGFBP3 promotes the proliferation of yak hepatocytes and enhances murine liver development by modulating the PI3K-Akt signaling pathway. The functional relevance of BgIGFBP3 was substantiated through in vivo and in vitro experiments, thereby underscoring its potential as a regulatory factor in liver development processes.