Quantification of putative ovarian cancer serum protein biomarkers using a multiplexed targeted mass spectrometry assay.

BACKGROUND: Ovarian cancer is the most lethal gynecologic malignancy in women, and high-grade serous ovarian cancer (HGSOC) is the most common subtype. Currently, no clinical test has been approved by the FDA to screen the general population for ovarian cancer. This underscores the critical need for the development of a robust methodology combined with novel technology to detect diagnostic biomarkers for HGSOC in the sera of women. Targeted mass spectrometry (MS) can be used to identify and quantify specific peptides/proteins in complex biological samples with high accuracy, sensitivity, and reproducibility. In this study, we sought to develop and conduct analytical validation of a multiplexed Tier 2 targeted MS parallel reaction monitoring (PRM) assay for the relative quantification of 23 putative ovarian cancer protein biomarkers in sera. METHODS: To develop a PRM method for our target peptides in sera, we followed nationally recognized consensus guidelines for validating fit-for-purpose Tier 2 targeted MS assays. The endogenous target peptide concentrations were calculated using the calibration curves in serum for each target peptide. Receiver operating characteristic (ROC) curves were analyzed to evaluate the diagnostic performance of the biomarker candidates. RESULTS: We describe an effort to develop and analytically validate a multiplexed Tier 2 targeted PRM MS assay to quantify candidate ovarian cancer protein biomarkers in sera. Among the 64 peptides corresponding to 23 proteins in our PRM assay, 24 peptides corresponding to 16 proteins passed the assay validation acceptability criteria. A total of 6 of these peptides from insulin-like growth factor-binding protein 2 (IBP2), sex hormone-binding globulin (SHBG), and TIMP metalloproteinase inhibitor 1 (TIMP1) were quantified in sera from a cohort of 69 patients with early-stage HGSOC, late-stage HGSOC, benign ovarian conditions, and healthy (non-cancer) controls. Confirming the results from previously published studies using orthogonal analytical approaches, IBP2 was identified as a diagnostic biomarker candidate based on its significantly increased abundance in the late-stage HGSOC patient sera compared to the healthy controls and patients with benign ovarian conditions. CONCLUSIONS: A multiplexed targeted PRM MS assay was applied to detect candidate diagnostic biomarkers in HGSOC sera. To evaluate the clinical utility of the IBP2 PRM assay for HGSOC detection, further studies need to be performed using a larger patient cohort.

Elevated serum IGFBP-1 levels correlate with cognitive deficits in treatment-resistant and chronic medicated schizophrenia patients.

BACKGROUND: Schizophrenia is a debilitating psychiatric disorder with diverse cognitive impairments. Insulin-like growth factor binding protein 1 (IGFBP-1), a ubiquitous negative regulator of IGF signaling, crosses the blood-brain barrier after peripheral synthesis. Given the crucial role of IGF signaling in cognitive function, we reasoned that altered serum IGFBP-1 concentrations might be associated with cognitive impairments in schizophrenia. To test this hypothesis, we examined the relationship between serum IGFBP-1 levels and cognitive performance in both medicated and treatment-resistant schizophrenia (TRS) patients. METHODS: Serum IGFBP-1 was measured in 31 TRS patients, 49 chronic medicated schizophrenia (CMS) patients, and 53 healthy controls. Clinical symptom severity was evaluated using the Positive and Negative Syndrome Scale (PANSS) and cognitive functions using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). RESULTS: Both TRS and CMS patients exhibited cognitive deficits compared to healthy controls (p < 0.05). Serum IGFBP-1 concentration differed significantly among groups (F=36.805, p < 0.001) and post hoc tests demonstrated significantly higher concentrations in both schizophrenia groups compared to controls (p < 0.001). Further, serum IGFBP-1 concentration was higher in the TRS group than the CMS group (p = 0.048). Correlation analysis identified a significant relationship between serum IGFBP-1 and attention in the TRS group (r = 0.411, p = 0.021), immediate memory in the CMS group (r = -0.417, p = 0.003), and RBANS total score in the CMS group (r = -0.368, p = 0.009). Multiple regression analysis adjusting for confounding factors revealed that serum IGFBP-1 was independently associated with attention in TRS patients (p = 0.016, 95 %CI. 0.002-0.015) and immediate memory in CMS patients (p = 0.022, 95 %CI-0.012 to -0.001). CONCLUSIONS: Elevated serum IGFBP-1 concentration may serve as a predictive biomarker for distinct cognitive deficits in TRS and CMS patients. Further investigations are warranted.

Chordin Like-1 Regulates Osteoblast and Adipocyte Differentiation Through Stabilizing Insulin-Like Growth Factor Binding Protein 3.

Chordin like-1 (CHRDL1) is an antagonist of bone morphogenetic proteins (BMPs) that acts through binding BMPs and blocking their interaction with BMP receptors. CHRDL1 plays a role in osteoblast differentiation but controversial effects were reported. On the other hand, the role of CHRDL1 in adipogenesis is unknown. In the present study, we investigated the function of CHRDL1 in regulating differentiation of osteoblasts and adipocytes and elucidated the underlying mechanism. CHRDL1 expression was downregulated during osteogenesis while it was upregulated during adipogenesis in primary cultured and established mesenchymal progenitor cell lines. Functional experiments revealed that CHRDL1 suppressed osteoblast differentiation and promoted adipocyte differentiation. Mechanistic explorations revealed that CHRDL1 is directly bound to insulin-like growth factor binding protein 3 (IGFBP3) and attenuated the degradation of the latter. Furthermore, CHRDL1 and IGFBP3 suppressed the activity of insulin receptor substrate 1 (IRS1)/AKT serine/threonine kinase (AKT)/mechanistic target of rapamycin kinase complex 1 (mTORC1) signaling in progenitor cells undergoing osteogenic differentiation. By contrast, they activated AKT/mTORC1 signaling independently of IRS1 during adipogenic differentiation. CHRDL1 enhanced the interaction of nuclear IGFBP3 and retinoid X receptor α (RXRα) during adipogenesis, and inhibition of RXR inactivated AKT and attenuated the stimulation of adipogenic differentiation by CHRDL1. Overexpression of IGFBP3 relieved the perturbation of osteogenic and adipogenic differentiation of progenitor cells induced by CHRDL1 silencing. Finally, CHRDL1 and IGFBP3 were upregulated in the trabecular bone of aged mice. Our study provides evidence that CHRDL1 reciprocally regulates osteoblast and adipocyte differentiation through stabilizing IGFBP3 and differentially modulating AKT/mTORC1 signaling.

IGFBP-rP1 is a potential therapeutic target in androgenic alopecia.

The available interventions for androgenic alopecia (AGA), the most common type of hair loss worldwide, remain limited. The insulin growth factor (IGF) system may play an important role in the pathogenesis of AGA. However, the exact role of IGF binding protein-related protein 1 (IGFBP-rP1) in hair growth and AGA has not been reported. In this study, we first found periodic variation in IGFBP-rP1 during the hair cycle transition in murine hair follicles (HFs). We further demonstrated that IGFBP-rP1 levels were lower in the serum and scalp HFs of individuals with AGA than in those of healthy controls. Subsequently, we verified that IGFBP-rP1 had no cytotoxicity to human outer root sheath cells (HORSCs) and that IGFBP-rP1 reversed the inhibitory effects of DHT on the migration of HORSCs in vitro. Finally, a DHT-induced AGA mouse model was created. The results revealed that the expression of IGFBP-rP1 in murine HFs was downregulated after DHT treatment and that subcutaneous injection of IGFBP-rP1 delayed catagen occurrence and prolonged the anagen phase of HFs in mice with DHT-induced AGA. The present work shows that IGFBP-rP1 is involved in hair cycle transition and exhibits great therapeutic potential for AGA.

Insulin-like growth factor binding protein-2 in at-risk adults and autopsy-confirmed Alzheimer brains.

Insulin, insulin-like growth factors (IGF) and their receptors are highly expressed in the adult hippocampus. Thus, disturbances in the insulin-IGF signaling pathway may account for the selective vulnerability of the hippocampus to nascent Alzheimer's disease (AD) pathology. In the present study, we examined the predominant IGF-binding protein (IGFBP) in the cerebrospinal fluid (CSF) - IGFBP2. CSF was collected from 109 asymptomatic members of the parental history-positive PREVENT-AD cohort. CSF levels of IGFBP2, core AD biomarkers and synaptic biomarkers were measured using proximity extension assay, ELISA and mass spectrometry. Cortical amyloid-beta (Aß) and tau deposition were examined using 18F-NAV4694 and flortaucipir. Cognitive assessments were performed up to 8 years of follow-up, using the Repeatable Battery for the Assessment of Neuropsychological Status. T1-weighted structural MRI scans were acquired, and neuroimaging analyses were performed on pre-specified temporal and parietal brain regions. Next, in an independent cohort, we allocated 241 dementia-free ADNI-1 participants into four stages of AD progression based on the biomarkers CSF Aß42 and total-tau (t-tau). In this analysis, differences in CSF and plasma IGFBP2 levels were examined across the pathological stages. Finally, IGFBP2 mRNA and protein levels were examined in the frontal cortex of 55 autopsy-confirmed AD and 31 control brains from the QFP cohort, a unique population isolate from Eastern Canada. CSF IGFBP2 progressively increased over 5 years in asymptomatic PREVENT-AD participants. Baseline CSF IGFBP2 was positively correlated with CSF AD biomarkers and synaptic biomarkers, and was negatively correlated with longitudinal changes in delayed memory (P = 0.024) and visuospatial abilities (P = 0.019). CSF IGFBP2 was negatively correlated at a trend-level with entorhinal cortex volume (P = 0.082) and cortical thickness in the piriform (P = 0.039), inferior temporal (P = 0.008), middle temporal (P = 0.014) and precuneus (P = 0.033) regions. In ADNI-1, CSF (P = 0.009) and plasma (P = 0.001) IGFBP2 were significantly elevated in Stage 2 (CSF Aß(+)/t-tau(+)). In survival analyses in ADNI-1, elevated plasma IGFBP2 was associated with a greater rate of AD conversion (HR = 1.62, P = 0.021). In the QFP cohort, IGFBP2 mRNA was reduced (P = 0.049), however IGFBP2 protein levels did not differ in the frontal cortex of autopsy-confirmed AD brains (P = 0.462). Nascent AD pathology may induce an upregulation in IGFBP2, in asymptomatic individuals. CSF and plasma IGFBP2 may be valuable markers for identifying CSF Aß(+)/t-tau(+) individuals and those with a greater risk of AD conversion.

Intrauterine botulinum toxin A administration promotes endometrial regeneration mediated by IGFBP3-dependent OPN proteolytic cleavage in thin endometrium.

Adequate endometrial growth is a critical factor for successful embryo implantation and pregnancy maintenance. We previously reported the efficacy of intrauterine administration of botulinum toxin A (BoTA) in improving the endometrial angiogenesis and the rates of embryo implantation. Here, we further evaluated its potent therapeutic effects on the uterine structural and functional repair and elucidated underlying molecular regulatory mechanisms. This study demonstrated that a murine model of thin endometrium was successfully established by displaying dramatically decreased endometrial thickness and the rates of embryo implantation compared to normal endometrium. Interestingly, the expressions of insulin-like growth factor binding protein-3 (IGFBP3) and an active 35 kDa-form of osteopontin (OPN) were significantly reduced in thin endometrium, which were almost fully restored by intrauterine BoTA administration. Neutralization of BoTA-induced IGFBP3 subsequently suppressed proteolytic cleavage of OPN, exhibiting un-recovered endometrial thickness even in the presence of BoTA administration, suggesting that BoTA-induced endometrial regeneration might be mediated by IGFBP3-dependent OPN proteolytic cleavage. Our findings suggest that intrauterine BoTA administration improves the endometrial environment in our murine model with thin endometrium by increasing endometrial receptivity and angiogenesis in a manner dependent on the regulatory effect of IGFBP3 on OPN proteolytic cleavage, proposing BoTA as an efficient therapeutic strategy for the patients with thin endometrium.

Insulin-Like Growth Factor-Binding Protein 5 Promotes the Cell Proliferation and Osteogenic Potential of Dental Pulp Stem Cells Dependent on Its Nuclear Localisation Sequence.

OBJECTIVES: Dental pulp stem cells (DPSCs) have been extensively used for tissue regeneration owing to their notable capabilities. Insulin-like growth factor-binding protein 5 (IGFBP5) regulates osteogenic differentiation of mesenchymal stem cells (MSCs); however, the underlying regulatory mechanisms require further investigation. MATERIALS AND METHODS: Carboxyfluorescein succinimidyl ester, an alkaline phosphatase (ALP) activity assay and Alizarin Red staining were used to reveal the role of IGFBP5 in DPSCs. Protein expression levels were determined using western blotting. Immunofluorescence was used to observe cell sub-localisation. Subcutaneous transplantation in nude mice was used to observe the osteogenesis of DPSCs in vivo. RESULTS: IGFBP5 enhanced the proliferation and osteogenic differentiation of DPSCs. Deletion of the nuclear localisation sequence (NLS) of IGFBP5 prevented its nuclear import and abolished all its promoting effects on DPSCs; ivermectin stimulation attenuated the enhancement of ALP activity by IGBFP5. Bone-like tissue formation promoted by IGFBP5 in vivo vanishes when the NLS is deleted. Inhibition of IGFBP5 nuclear import attenuated the IGFBP5-induced phosphorylation of JNK (p-JNK) and phosphorylated ERK (p-ERK) in DPSCs. CONCLUSION: Our findings suggest that cell proliferation and osteogenic differentiation effects exerted by IGFBP5 on DPSCs are closely associated with their entry into the nucleus, thereby providing a novel potential target for tissue regeneration.

The IGF-PAPP-A-Stanniocalcin Axis in Serum and Ascites Associates with Prognosis in Patients with Ovarian Cancer.

Pregnancy-associated plasma protein-A (PAPP-A) and PAPP-A2 modulate insulin-like growth factor (IGF) action and are inhibited by the stanniocalcins (STC1 and STC2). We previously demonstrated increased PAPP-A and IGF activity in ascites from women with ovarian carcinomas. In this prospective, longitudinal study of 107 women with ovarian cancer and ascites accumulation, we determined corresponding serum and ascites levels of IGF-1, IGF-2, PAPP-A, PAPP-A2, STC1, and STC2 and assessed their relationship with mortality. As compared to serum, we found highly increased ascites levels of PAPP-A (51-fold) and PAPP-A2 (4-fold). Elevated levels were also observed for IGF-1 (12%), STC1 (90%) and STC2 (68%). In contrast, IGF-2 was reduced by 29% in ascites. Patients were followed for a median of 38.4 months (range: 45 days to 8.9 years), during which 73 patients (68.2%) died. Overall survival was longer for patients with high serum IGF-1 (hazard ratio (HR) per doubling in protein concentration: 0.60, 95% CI: 0.40-0.90). However, patients with high ascites levels of IGF-1 showed a poorer prognosis (HR: 2.00 (1.26-3.27)). High serum and ascites IGF-2 levels were associated with increased risk of mortality (HR: 2.01 (1.22-3.30) and HR: 1.78 (1.24-2.54), respectively). Similarly, serum PAPP-A2 was associated with mortality (HR: 1.26 (1.08-1.48)). Our findings demonstrate the presence and activity of the IGF system in the local tumor ecosystem, which is likely a characteristic feature of malignant disease and plays a role in its peritoneal dissemination. The potential clinical implications are supported by our finding that serum levels of the proteins are associated with patient prognosis.

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.

Insulin-like growth factor binding protein-3 (igfbp-3) and igfbp-5 in yellowtail kingfish (Seriola lalandi): molecular characterization and expression levels under different nutritional status and stocking density.

Insulin-like growth factor-binding proteins (IGFBPs) play important roles in regulating growth and development by binding to IGF, where IGFBP-3 and IGFBP-5 are the main binding carriers of IGF in the circulation system. In the present study, the gene sequences of igfbp-3, igfbp-5a, and igfbp-5b were cloned from the liver of yellowtail kingfish (Seriola lalandi). The ORF sequences of igfbp-3, igfbp-5a, and igfbp-5b were 888, 801, and 804 bp in length, which encoded 295, 266, and 267 amino acids, respectively. The above three genes were widely expressed in yellowtail kingfish tissues, with igfbp-3 being the most highly expressed in the heart, brain, and gonads, while igfbp-5a and igfbp-5b were both most highly expressed in the liver and kidney. The expression levels of igfbp-3, igfbp-5a, and igfbp-5b were detected throughout the embryonic and larval stages, suggesting their roles in early development and growth regulation of yellowtail kingfish. Besides, igfbp-3 and igfbp-5a were significantly up-regulated in the liver under food deprivation and high-density rearing conditions, which was exactly opposite to the growth performance of yellowtail kingfish, implying that they may serve as biomarkers of adverse culture conditions. Overall, the above results initially identified the molecular characteristics of igfbp-3/-5a/-5b in yellowtail kingfish and implied that they might play important roles in the growth and development, providing a basis for further research on underlying regulatory mechanisms.

Associations of insulin-like growth factor binding protein-2 with metabolic profile and hepatic fat deposition in asymptomatic men and women.

Low circulating levels of insulin-like growth-factor binding protein-2 (IGFBP-2) have been associated with increased adiposity and metabolic alterations such as insulin resistance, dyslipidemia, and nonalcoholic fatty liver disease in individuals with obesity. However, whether IGFBP-2 affects energy metabolism in the early stages of these disorders remains unclear. Herein, we hypothesized that plasma IGFBP-2 concentrations are inversely associated with early liver fat accumulation and alterations in lipid and glucose homeostasis in apparently healthy and asymptomatic men and women. Three hundred thirty-three middle-aged Caucasian men and women apparently healthy and without cardiovascular symptoms were enrolled for a cross-sectional cardiometabolic imaging study. Individuals with BMI ≥ 40 kg/m2, cardiovascular disease, dyslipidemia, hypertension, and diabetes were excluded. Fasting glucose and lipid profiles were measured and an oral glucose tolerance test was performed. Liver fat content was assessed by magnetic resonance spectroscopy. Volume of visceral adipose tissue (VAT) was evaluated by magnetic resonance imaging. Plasma IGFBP-2 levels were quantified by ELISA. Participants with low IGFBP-2 levels were characterized by a higher body fat mass (P < 0.0001), insulin resistance (P < 0.0001), higher plasma triglyceride (TG) (P < 0.0001), and lower HDL-cholesterol levels (P < 0.0001) in a sex-independent manner. IGFBP-2 levels were inversely correlated with hepatic fat fraction in both men (r = -0.36, P < 0.0001) and women (r = -0.40, P < 0.0001). IGFBP-2 concentrations were negatively associated with hepatic fat fraction independently of age and VAT in both men (R2 = 0.23, P = 0.012) and women (R2 = 0.27, P = 0.028). In conclusion, our findings show that even in asymptomatic, apparently healthy individuals, low IGFBP-2 levels are associated with a more deteriorated cardiometabolic risk profile and with a high hepatic fat content in a VAT-independent manner. However, IGFBP-2 does not appear to influence the established sexual dimorphism observed for metabolic variables and hepatic fat fraction. Additional studies are required to better understand the relationships between IGFBP-2 and liver fat content.NEW & NOTEWORTHY Faced with a paucity of reliable clinical etiologic markers for fatty liver, this research article demonstrates, for the first time, that low blood levels of the protein IGFBP-2 are associated with a more deteriorated cardiometabolic risk profile and with a high hepatic fat content independently of visceral fat volume and sex, even in asymptomatic, apparently healthy individuals.

Potent antitumor effects of the conditioned medium of bone marrow-derived mesenchymal stem cells via IGFBP-4.

Cell transfer therapy using mesenchymal stem cells (MSCs) has pronounced therapeutic potential, but concerns remain about immune rejection, emboli formation, and promotion of tumor progression. Because the mode of action of MSCs highly relies on their paracrine effects through secretion of bioactive molecules, cell-free therapy using the conditioned medium (CM) of MSCs is an attractive option. However, the effects of MSC-CM on tumor progression have not been fully elucidated. Herein, we addressed this issue and investigated the possible underlying molecular mechanisms. The CM of MSCs derived from human bone marrow greatly inhibited the in vitro growth of several human tumor cell lines and the in vivo growth of the SCCVII murine squamous cell carcinoma cell line with reduced neovascularization. Exosomes in the MSC-CM were only partially involved in the inhibitory effects. The CM contained a variety of cytokines including insulin-like growth factor binding proteins (IGFBPs). Among them, IGFBP-4 greatly inhibited the in vitro growth of these tumors and angiogenesis, and immunodepletion of IGFBP-4 from the CM significantly reversed these effects. Of note, the CM greatly reduced the phosphorylation of AKT, ERK, IGF-1 receptor beta, and p38 MAPK in a partly IGFBP4-dependent manner, possibly through its binding to IGF-1/2 and blocking the signaling. The CM depleted of IGFBP-4 also reversed the inhibitory effects on in vivo tumor growth and neovascularization. Thus, MSC-CM has potent inhibitory effects on tumor growth and neovascularization in an IGFBP4-dependent manner, suggesting that cell-free therapy using MSC-CM could be a safer promising alternative for even cancer patients.

Interventions, Barriers, and Proposed Solutions Associated With the Implementation of a Protocol That Uses Clinical Decision Support and a Stress Biomarker Test to Identify ICU Patients at High-Risk for Drug Associated Acute Kidney Injury.

BACKGROUND: Damage biomarkers are helpful in early identification of patients who are at risk of developing acute kidney injury (AKI). Investigations are ongoing to identify the optimal role of stress/damage biomarkers in clinical practice regarding AKI risk prediction, surveillance, diagnosis, and prognosis. OBJECTIVE: To determine the impact of utilizing a clinical decision support system (CDSS) to guide stress biomarker testing in intensive care unit (ICU) patients at risk for drug-induced acute kidney injury (D-AKI). METHODS: A protocol was designed utilizing a clinical decision support system (CDSS) alert to identify patients that were ordered 3 or more potentially nephrotoxic medications, suggesting risk for progressing to AKI from nephrotoxic burden. Once alerted to these high-risk patients, the pharmacist determined if action was needed by ordering a stress biomarker test, tissue inhibitor of metalloproteinase-2-insulin-like growth factor-binding protein 7 (TIMP-2•IGFBP7). If the biomarker test result was elevated, the pharmacist provided nephrotoxin stewardship recommendations to the team. Pharmacists recorded the response to the clinical decision support alert, ordering, and interpreting the TIMP-2•IGFBP7, and information regarding clinical interventions. An alert in conjunction with TIMP-2•IGFBP7 as a strategy for AKI risk prediction and stimulant for patient care management was assessed. In addition, barriers and solutions to protocol implementation were evaluated. RESULTS: There were 394 total activities recorded by pharmacists for 345 unique patients. Ninety-three (93/394; 23.6%) actionable alerts resulted in a TIMP-2•IGFBP7 test being ordered. Thirty-one TIMP-2•IGFBP7 results were >0.3 (31/81; 38.3%), suggesting a high-risk of progression to AKI, which prompted 191 pharmacist/team interventions. On average, there were 1.64 interventions per patient in the low-risk patients, 3.43 in high-risk patients, and 3.75 in the highest-risk patients. CONCLUSION AND RELEVANCE: Stress biomarkers can be used in conjunction with CDSS alerts to affect therapeutic decisions in ICU patients at high-risk for D-AKI.

Expression of insulin-like growth factor binding protein-3 in HELLP syndrome.

OBJECTIVE: To investigate the expression of insulin-like growth factor binding protein-3(IGFBP-3) in HELLP syndrome and its possible role in the pathogenesis of this disease. METHODS: 1) 87 subjects were enrolled, including 29 patients with HELLP syndrome, 29 patients with pre-eclampsia (PE), and 29 healthy gravidae as control. The levels of IGFBP-3, IGF-1, TGF-ß1, and VEGF in maternal and umbilical blood of them were detected using ELISA. Correlation analysis was used to observe the correlation between IGFBP-3 and IGF-1/TGF-ß1/VEGF in maternal and umbilical blood, as well as that between maternal serum IGFBP-3 and clinical diagnostic indicators of HELLP syndrome. 2) Human hepatic sinusoid endothelial cells (HLSEC) and human umbilical vein endothelial cells (HUVEC) were cultured with different concentrations of IGFBP-3. After 72 h of culture, cell apoptosis and the normal living cells rate were detected and compared. RESULTS: 1) In both maternal and umbilical blood of HELLP group, levels of IGFBP-3 and TGF-ß1 were higher than control and PE group, IGF-1was lower than control group, VEGF was lower than control and PE group. IGFBP-3 in maternal blood was correlated with IGF-1/TGF-ß1/ VEGF, while IGFBP-3 in umbilical blood was linked to IGF-1/TGF-ß1. In maternal blood, there was a negative correlation between PLT and IGFBP-3, and a positive correlation between ALT/AST/LDH and IGFBP-3. 2) After cultured with IGFBP-3, the total apoptosis rate of either HLSEC or HUVEC was considerably elevated, while the normal living rate was decreased. CONCLUSION: The expression of IGFBP-3 is elevated in HELLP syndrome, which may subsequently promote cell apoptosis by affecting the expression and function of IGF-1, VEGF, and TGFß1 in the IGF/PI3K/Akt, TGF-ß1/Smad3, and VEGF/eNOS/NO pathways. IGFBP-3 aggravates inflammatory reactions of the vascular endothelium and liver under hypoxia, affects the normal function of cells, and plays a role in the pathogenesis of diseases.

Urinary cell cycle biomarkers for the prediction of renal non-recovery in patients with septic acute kidney injury: a prospective study.

BACKGROUND: Poor prognosis has been associated with the absence of renal recovery after acute kidney injury (AKI). This study aimed to investigate whether urinary biomarkers at 0 and 24 h could be used independently or in conjunction with a clinical model to predict renal non-recovery in septic AKI. METHODS: A prospective observational study was conducted to measure the urinary levels of insulin-like growth factor-binding protein 7 (IGFBP7) and tissue inhibitor of metalloproteinase-2 (TIMP-2) at the time of AKI diagnosis (0 h) and 24 h later. Renal non-recovery within 7 days was defined as the outcome. The predictive value of urinary biomarkers for renal non-recovery in septic AKI was assessed using the area under the curve (AUC). RESULTS: A total of 198 individuals with septic AKI were included in the final analysis. Among them, 38.9% (n = 77) did not experience renal recovery within 7 days. The combination of urinary IGFBP7 and TIMP-2 at the initial time point demonstrated prognostic value for non-recovery of renal function, with an AUC of 0.782. When [TIMP-2]*[IGFBP7] was measured at 0 h, the clinical prognostic model, incorporating AKI stage 2-3 and the non-renal sequential organ failure assessment score, showed an improved AUC of 0.822 (with a sensitivity of 88.3% and specificity of 59.5%). CONCLUSIONS: The combination of urinary [TIMP-2]*[IGFBP7] at 0 h exhibited moderate predictive ability for renal non-recovery in cases of septic AKI. However, there is potential to enhance the prognostic capabilities of the [TIMP-2]*[IGFBP7]-clinical prediction model.

A bacteria-regulated gut peptide determines host dependence on specific bacteria to support host juvenile development and survival.

BACKGROUND: Commensal microorganisms have a significant impact on the physiology of host animals, including Drosophila. Lactobacillus and Acetobacter, the two most common commensal bacteria in Drosophila, stimulate fly development and growth, but the mechanisms underlying their functional interactions remain elusive. RESULTS: We found that imaginal morphogenesis protein-Late 2 (Imp-L2), a Drosophila homolog of insulin-like growth factor binding protein 7, is expressed in gut enterocytes in a bacteria-dependent manner, determining host dependence on specific bacteria for host development. Imp-L2 mutation abolished the stimulatory effects of Lactobacillus, but not of Acetobacter, on fly larval development. The lethality of the Imp-L2 mutant markedly increased under axenic conditions, which was reversed by Acetobacter, but not Lactobacillus, re-association. The host dependence on specific bacteria was determined by Imp-L2 expressed in enterocytes, which was repressed by Acetobacter, but not Lactobacillus. Mechanistically, Lactobacillus and Acetobacter differentially affected steroid hormone-mediated Imp-L2 expression and Imp-L2-specific FOXO regulation. CONCLUSIONS: Our finding may provide a way how host switches dependence between different bacterial species when benefiting from varying microbiota.

The predictive value of [TIMP-2]*[IGFBP7] in adverse outcomes for acute kidney injury: a systematic review and meta-analysis.

MATERIALS AND METHODS: Relevant articles published up to 17 June 2023 were retrieved from five databases (Cochrane Library/Embase/PubMed/SinoMed/Web of Science). The pre-established inclusion and exclusion criteria determined the selection of publications. Pooled sensitivity (SEN), specificity (SPE), diagnostic odds ratio, likelihood ratio, and summary receiver operating characteristic curve were employed to assess the predictive value. The presence or potential sources of heterogeneity were investigated via subgroup and SEN analyses. RESULTS: Ten published and eligible studies (1559 cases) were included in the evaluation for the capability of [TIMP-2]*[IGFBP7] to predict the poor prognosis of AKI through the random effect model. Pooled SEN, SPE, diagnostic odds ratio, and positive and negative likelihood ratios were 0.82 (95% CI: 0.77-0.86, I2 = 53.4%), 0.64 (95% CI: 0.61-0.67, I2 = 88.3%), 14.06 (95% CI: 7.31-27.05, I2 = 55.0%), 2.859 (95% CI: 2.15-3.77, I2 = 80.7%), and 0.28 (95% CI: 0.20-0.40, I2 = 35.0%), respectively. The estimated area under the curve was 0.8864 (standard error: 0.0306), and the Q* was 0.7970 (standard error: 0.0299). The endpoints and cutoff values were the main causes of heterogeneity. CONCLUSIONS: [TIMP-2]*[IGFBP7] is possible in predicting poor prognosis of AKI, but it is better to be applied along with other indicators or clinical risk factors.

Insulin-like growth factor binding protein 5 accelerate the senescence of periodontal ligament stem cells.

Evidences have showed stem cell mediated tissue regeneration is a promising method for the treatment of periodontitis. Insulin-like growth factor binding proteins-5 (IGFBP5) is a member of the insulin growth factor (IGFs) family and plays a regulatory role in cell proliferation and differentiation. Our previous study showed that IGFBP5 can promote osteogenic differentiation of periodontal ligament stem cells (PDLSCs) and enhance periodontal tissue regeneration mediated by PDLSCs. However, the function of IGFBP5 in the process of PDLSCs senescence remains unclear. The present study showed IGFBP5 mRNA level was highly expressed in passage-induced aged PDLSCs cells. IGFBP5 knockdown decreased the ratio of senescence associated ß-galactosidase (SA-ß-Gal) positive cells, enhanced the activity of TERT, and down-regulated the expression levels of P16, P21, P53 mRNA and protein. Overexpression of IGFBP5 increased the ratio of SA-ß-Gal positive staining PDLSCs, decreased the activity of telomerase TERT, and up-regulated the expression levels of P16, P21, P53 mRNA and protein related to PDLSCs senescence. In conclusion, IGFBP5 can accelerate the senescence of PDLSCs, indicating the potential target for maintaining the "young state" of stem cells.

Protein Plasma Levels of the IGF Signalling System Are Altered in Major Depressive Disorder.

The Insulin-like growth factor 2 (IGF-2) has been recently proven to alleviate depressive-like behaviors in both rats and mice models. However, its potential role as a peripheral biomarker has not been evaluated in depression. To do this, we measured plasma IGF-2 and other members of the IGF family such as Binding Proteins (IGFBP-1, IGFBP-3, IGFBP-5 and IGFBP-7) in a depressed group of patients (n = 51) and in a healthy control group (n = 48). In some of these patients (n = 15), we measured these proteins after a period (19 ± 6 days) of treatment with antidepressants. The Hamilton Depressive Rating Scale (HDRS) and the Self-Assessment Anhedonia Scale (SAAS) were used to measure depression severity and anhedonia, respectively. The general cognition state was assessed by the Mini-Mental State Examination (MMSE) test and memory with the Free and Cued Selective Reminding Test (FCSRT). The levels of both IGF-2 and IGFBP-7 were found to be significantly increased in the depressed group; however, only IGF-2 remained significantly elevated after correction by age and sex. On the other hand, the levels of IGF-2, IGFBP-3 and IGFBP-5 were significantly decreased after treatment, whereas only IGFBP-7 was significantly increased. Therefore, peripheral changes in the IGF family and their response to antidepressants might represent alterations at the brain level in depression.

Serum IGFBP-1 Concentration as a Predictor of Outcome after Ischemic Stroke-A Prospective Observational Study.

Insulin-like growth factor-binding protein-1 (IGFBP-1) regulates insulin-like growth factor-I (IGF-I) bioactivity, and is a central player in normal growth, metabolism, and stroke recovery. However, the role of serum IGFBP-1 (s-IGFBP-1) after ischemic stroke is unclear. We determined whether s-IGFBP-1 is predictive of poststroke outcome. The study population comprised patients (n = 470) and controls (n = 471) from the Sahlgrenska Academy Study on Ischemic Stroke (SAHLSIS). Functional outcome was evaluated after 3 months, 2, and 7 years using the modified Rankin Scale (mRS). Survival was followed for a minimum of 7 years or until death. S-IGFBP-1 was increased after 3 months (p < 0.01), but not in the acute phase after stroke, compared with the controls. Higher acute s-IGFBP-1 was associated with poor functional outcome (mRS score > 2) after 7 years [fully adjusted odds ratio (OR) per log increase 2.9, 95% confidence interval (CI): 1.4-5.9]. Moreover, higher s-IGFBP-1 after 3 months was associated with a risk of poor functional outcome after 2 and 7 years (fully adjusted: OR 3.4, 95% CI: 1.4-8.5 and OR 5.7, 95% CI: 2.5-12.8, respectively) and with increased mortality risk (fully adjusted: HR 2.0, 95% CI: 1.1-3.7). Thus, high acute s-IGFBP-1 was only associated with poor functional outcome after 7 years, whereas s-IGFBP-1 after 3 months was an independent predictor of poor long-term functional outcome and poststroke mortality.