Search

Periodontitis is a complex disease characterized by distinct inflammatory stages, with a peak of inflammation in the early phase and less prominent inflammation in the advanced phase. The insulin-like growth factor 2-binding proteins 2 (IGF2BP2) has recently been identified as a new m6A reader that protects m6A-modified messenger RNAs (mRNAs) from decay, thus participating in multiple biological processes. However, its role in periodontitis remains unexplored. Here, we investigated the role of IGF2BP2 in inflammation and osteoclast differentiation using a ligature-induced periodontitis model. Our findings revealed that IGF2BP2 responded to bacterial-induced inflammatory stimuli and exhibited differential expression patterns in early and advanced periodontitis stages, suggesting its dual role in regulating this disease. Depletion of Igf2bp2 contributed to increased release of inflammatory cytokines, thereby exacerbating periodontitis after 3 d of ligature while suppressing osteoclast differentiation and ameliorating periodontitis after 14 d of ligature. Mechanistically, we demonstrated that IGF2BP2 directly interacted with Cd5l and Cd36 mRNA via RNA immunoprecipitation assay. Overexpression of CD36 or recombinant CD5L rescued the osteoclast differentiation ability of Igf2bp2 -null cells upon lipopolysaccharide stimulus, and thus the downregulation of Cd36 and Cd5l effectively reversed periodontitis in the advanced stage. Altogether, this study deepens our understanding of the potential mechanistic link among the dysregulated m6A reader IGF2BP2, immunomodulation, and osteoclastogenesis during different stages of periodontitis. [ABSTRACT FROM AUTHOR]

Overexpression of pathogenic membrane proteins drives abnormal proliferation and invasion of tumor cells. Various strategies to durably knockdown membrane proteins with heterobifunctional degraders have been successfully developed, including LYTAC, KineTAC, and AbTAC. However, challenges including complicated synthetic procedures and the inability to simultaneously degrade multiple pathogenic proteins still exist. Herein, we developed insulin‐like growth factor 2 (IGF2)‐tagged aptamer chimeras (ITACs) that link the cell‐surface lysosome‐targeting receptor IGF2R and membrane proteins of interest (POIs) based on specific recognition of aptamers to the POIs and high‐affinity binding of IGF2 to IGF2R. We demonstrated that ITACs exhibit robust degradation efficiency of various membrane proteins in multiple cell lines. Furthermore, systematic studies revealed that a moderate cell‐surface IGF2R level is responsible for the excellent degradation performance of ITACs. Importantly, we further established a modular assembly strategy that allows assembly of one IGF2 with two aptamers with precise stoichiometry (dITACs), enabling cooperative and simultaneous degradation of two membrane proteins. This work provides an efficient and facile target membrane protein degradation platform and will shed light on the treatment of diseases related to the overexpression of membrane proteins. [ABSTRACT FROM AUTHOR]

Objective: To explore the changes of serum-related indexes at different time points, so as to identify the critical time of converting from simple premature thelarche (PT) to idiopathic central precocious puberty (ICPP). Methods: This is a retrospective study. The subjects of the study were 50 girls with PT who were admitted to the Children's Hospital of Hebei Province from January 2019 to September 2020. The enrolled 50 children were divided into the conversion group(n=12) and the non-conversion group(n=38) according to whether PT was converted into ICPP during follow-up. Furthermore, the levels of serum-related indexes and uterine and ovarian volumes were compared after the diagnosis of PT. Results: The IGF-1 and IGFBP-3 levels of children in the conversion group began to change significantly from six months after the diagnosis, with statistically significant differences when compared with the levels of children at the initial diagnosis, three months and those of the non-conversion group at the same time points (p<0.05). The levels of vitamin-D, DHEA and leptin began to change significantly at nine months after the diagnosis (p<0.05). Besides, uterine and ovarian volumes in the conversion group began to increase significantly six months after the diagnosis, with statistically significant differences when compared with those in the non-conversion group (p<0.05). Conclusion: Findings in our study suggest that regular monitoring of vitamin-D, IGF-1, IGFBP-3, DHEA and leptin levels, and uterine and ovarian volumes can predict the conversion from PT to ICPP at an early stage. [ABSTRACT FROM AUTHOR]

Simple Summary: In this study, transcriptome sequencing was first performed on the brain, liver, and muscle tissues of 3-month-old M. armatus individuals with different growth rates. A number of growth-related genes and biological pathways that related to skeletal muscle tissue development and insulin-like growth factor binding were screened. Our results suggest that IGFBP-1A, IGFBP-1B, GH, and GHR play an important role in the early developmental stage of M. armatus. These results contribute to providing a reference for further studies on the molecular mechanism of growth and development in teleost fish. In order to explore the main regulatory genes and related pathways of growth traits, transcriptome sequencing was first performed on the brain, liver, and muscle tissues of 3-month-old M. armatus with different growth rates. By comparative transcriptome analysis of fast-growing and slow-growing groups of M. armatus, a total of 2887 DEGs were screened, of which 59 up-regulated genes and 105 down-regulated genes were detected in the brain, 146 up-regulated genes and 202 down-regulated genes were detected in the liver, and 529 up-regulated genes and 1846 down-regulated genes were detected in muscle, including insulin-like growth factor binding protein 1a (IGFBP1A), insulin-like growth factor binding protein 1b (IGFBP1B), myosin, light chain 1 (MYL1), and myoglobin (MB). Through Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis, we identified a total of 288 significantly enriched GO entries and 68 significantly enriched KEGG pathways related to growth, such as skeletal muscle tissue development, insulin-like growth factor binding, and the mitotic cell cycle. These key genes and signaling pathways may play a key role in regulating the growth of M. armatus. Digging into the regulatory mechanisms of these key genes will provide a theoretical basis for further exploration of the molecular mechanisms related to the growth and development of M. armatus, and help to breed new varieties of M. armatus with rapid growth. [ABSTRACT FROM AUTHOR]

The ongoing challenges of climate change and pollution are major factors disturbing ecosystems, including aquatic systems. They also have an impact on gene regulation and biochemical changes in aquatic animals, including fish. Understanding the mechanisms of gene regulation and biochemical changes due to climate change and pollution in aquatic animals is a challenging task. However, with this backdrop, the present investigation was conducted to explore the effects of arsenic (As) and ammonia (NH3) toxicity and high-temperature (T) stress on gene regulation and biochemical profiles, mitigated by dietary manganese (Mn) in Pangasianodon hypophthalmus. The fish were exposed to different combinations of As, NH3, and T, and fed with dietary Mn at 4, 8, and 12 mg kg−1 to evaluate the gene expression of immunity, antioxidative status, cytokine, and NfKB signaling pathway genes. HSP 70, cytochrome P450 (CYP 450), metallothionein (MT), DNA damage-inducible protein (DDIP), caspase (CAS), tumor necrosis factor (TNFα), toll-like receptor (TLR), interleukin (IL), inducible nitric oxide synthase (iNOS), catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GPx) were noticeably highly upregulated by As + NH3 + T stress, whereas Mn diet at 8 mg kg−1 downregulated these genes. Further, total immunoglobulin (Ig), myostatin (MYST), somatostatin (SMT), growth hormone (GH), growth hormone regulator 1 and β, insulin-like growth factors (IGF1X1 and IGF1X2) were significantly upregulated by Mn diets. The biochemical profiles were highly affected by stressors (As + NH3 + T). The bioaccumulation of arsenic in different tissues was also notably reduced by Mn diets. Furthermore, the infectivity of the fish was reduced, and survival against pathogenic bacteria was enhanced by Mn diet at 8 mg kg−1. The results of the present investigation revealed that dietary Mn at 8 mg kg−1 controls gene regulation against multiple stressors (As, NH3, As + NH3, NH3 + T, As + NH3 + T) in fish. [ABSTRACT FROM AUTHOR]

Background: Recombinant human growth hormone (rhGH) therapy is beneficial for children with Prader–Willi syndrome (PWS) in improving short stature and metabolism, but the effect of early rhGH treatment on respiratory and sleep parameters for PWS children under three years old remains elusive. Thus, this study aimed to investigate the impact of rhGH treatment on sleep-related breathing disorders (SRBDs) for toddlers with PWS. Methods: A total of 17 age-matched PWS patients receiving rhGH treatment (rhGH group) and 17 control individuals not receiving rhGH treatment (non-rhGH group) were recruited for this study between October 2018 and January 2023. Data related to polysomnography-polygraphy (PSG) and serum levels of insulin-like growth factor (IGF-1) and insulin-like growth factor binding protein 3 (IGFBP-3) were collected. Results: The mean age in the rhGH group was 20.76 ± 9.22 months, which was comparable to that of the non-rhGH group (25.23 ± 13.81 months). The demographic and anthropometric parameters were similar across the two groups after 52 weeks of treatment. Administration of rhGH to toddlers did not exert adverse effects on the obstructive apnea–hypopnea index (OAHI), central apnea index (CAI), oxygen desaturation index (ODI), mean percutaneous oxygen saturation (SpO2), lowest SpO2, duration when SpO2 is lower than 90%, or proportion of the patients with SpO2 lower than 90%. Furthermore, the increased IGF-1 z-score and IGFBP-3 level did not worsen SRBDs. Conclusion: Treatment with rhGH for 52 weeks on young toddlers with PWS showed no deleterious effects on SRBDs. This shed more light on the importance of initiating rhGH therapy early in PWS patients. [ABSTRACT FROM AUTHOR]

The purpose of this study was to examine the genetic makeup of insulin-like growth factor-2 (IGF-2) and its impact on the various components of blood cells. This study utilized a total of 300 broiler chicks, aged one day, from two different strains: 150 chicks from the Cobb 500 strain and 150 chicks from the Hubbard F - 15 strain. Genomic material was isolated from avian blood samples, and the constituent elements of the blood were analyzed. The blood components were cytologically examined and their genotypes for insulin-like growth factor-2 (IGF-2) were determined using PCR-RFLP. The study observed a notable rise (p≤0.05) in the level of Hb in the bloodstream of females (p≤0.05) with the genotypes TT and CC. The findings indicated a statistically significant increase (p≤0.05) in the PCV% of females with the CC genotype compared to those with the TT and TC genotypes. The findings also indicated that there were no statistically significant variations (p≤0.05) in the mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), and mean corpuscular hemoglobin concentration (MHCV) across the different genotypes. The IGF2 gene incorporates variables related to ethnicity and sex. The number of Heterophil cells in the offspring of the Cobb500 strain with the TC genotype was significantly higher (p≤0.05) compared to the TT and CC models. Additionally, there was a significant increase (p≤0.05) in the number of Heterophil cells in males with the TC genotype compared to the TT and CC models, while this increase was not observed in other cases. The IGF2 gene genotypes exhibit notable variations in both lymphocyte count and the H/L ratio. Multiple genotypes of the IGF-2 insulin-like growth factor gene were discovered to have a notable impact on the quantity of eosinophil cells in the Hubbard F -15 strain. This effect was observed in males of all genotypes involved in the experiment. The experiment revealed a notable rise in the count of basophil cells among females with the CC genotype compared to individuals with other genotypes. However, there were no significant variations in the number of basophil cells (p≤0.05) among individuals with other genotypes or between the two strains. The results did not show a statistically significant difference in the number of monocyte cells or in any of the IGF2 genotypes, taking into account the influence of strain and sex. [ABSTRACT FROM AUTHOR]

Aims: Growth differentiation factor‐15 (GDF‐15) is upregulated in part in response to cardiomyocyte stretch and stress, and it exerts a protective role that is mediated by its action to suppress signalling through insulin‐like growth factor (IGF) and enhance signalling through adenosine monophosphate‐activated protein kinase (AMPK). Sodium–glucose cotransporter 2 (SGLT2) inhibitors improve outcomes in heart failure, which has been experimentally linked to AMPK. This study aimed at evaluating the associations of GDF‐15 with baseline characteristics, the prognostic significance of GDF‐15, and the effect of empagliflozin on GDF‐15 in patients with heart failure with a reduced and preserved ejection fraction. Methods and results: Growth differentiation factor‐15 was determined in serum samples from the EMPEROR‐Reduced and EMPEROR‐Preserved trials. Cox regression and mixed models for repeated measures were used to study the association with outcomes and the effect of empagliflozin on GDF‐15, respectively. We studied 1124 patients (560 placebo and 564 empagliflozin) with median GDF‐15 levels at baseline of 2442 (interquartile range 1603–3780) pg/ml. Patients with higher GDF‐15 levels were typically older men with more severe symptoms, higher N‐terminal pro‐B‐type natriuretic peptide levels, worse kidney function and who were prescribed metformin. Baseline levels of GDF‐15 were well correlated with levels of IGF‐binding protein 7 (rho = 0.64). Higher levels of GDF‐15 were independently associated with an increased risk of cardiovascular death, heart failure hospitalizations, and worse kidney outcomes. When considered as a continuous variable, for each doubling in GDF‐15, the adjusted hazard ratio for cardiovascular death or heart failure hospitalization was 1.40 (95% confidence interval 1.15–1.71; p < 0.001). The relative effect of empagliflozin on cardiovascular death and hospitalization for heart failure was most pronounced in patients with higher baseline levels of GDF‐15 (interaction p‐trend = 0.031). At week 52, when compared with placebo, empagliflozin increased GDF‐15 by an additional 8% (p = 0.020), an effect that was primarily seen in patients not receiving metformin, a known AMPK activator. Conclusions: Growth differentiation factor‐15 is a marker of worse heart failure severity, is an independent predictor of major heart failure outcomes and may be associated with more pronounced benefits of empagliflozin. GDF‐15 is increased among metformin users, and empagliflozin was associated with an increase in GDF‐15 levels, primarily in patients not receiving metformin. [ABSTRACT FROM AUTHOR]

Background/aim: Atopic dermatitis (AD) is an inflammatory, pruritic, noncontagious, chronic relapsing skin disease. Skin barrier abnormalities, excessive T helper 2 activity, and immune dysregulation are held responsible. Androgens have a negative effect on the integrity of the epidermal skin barrier, while estrogen has a positive effect. We aimed to investigate whether hormones make a difference between healthy children and children with AD during minipuberty. Materials and methods: A total of 96 infants (postnatal 4-13 weeks), 48 diagnosed with AD and 48 controls, were included. Each group consisted of 23 girls (47.9%) and 25 boys (52.1%). Anthropometric examinations and hormone measurements were compared. Results: The two groups, having similar age, sex, body mass index, and weight-for-length standard deviation scores, were compared. Serum free thyroxine (FT4) levels were found to be lower and insulin-like growth factor binding protein-3 (IGFBP3) levels were found to be higher in children with AD (p < 0.001 and p = 0.038, respectively). In girls with AD, estradiol, FT4, and insulin-like growth factor-1 (IGF-1) levels were found to be lower, but thyroid-stimulating hormone (TSH) levels were found to be higher (p = 0.023, p < 0.001, p = 0.038, and p = 0.034, respectively). In boys with AD, the FT4 level was found to be lower (p = 0.023). Serum FT4 and TSH levels were within normal reference ranges in all comparisons. Conclusion: Especially in girls with AD, decreased estradiol and IGF-1 levels were observed compared to the controls during minipuberty. In the logistic regression model, decreased levels of serum estradiol, dehydroepiandrosterone sulfate, FT4, and IGF-1, and increased levels of IGFBP3 were associated with an increased likelihood of exhibiting atopic dermatitis. [ABSTRACT FROM AUTHOR]

Altered methylation patterns of insulin-like growth factor (IGF)-axis genes in small for gestational age (SGA) have been reported in different populations. In the present study, we analyzed the methylation status of IGF-axis genes in the placenta of appropriate for gestational age (AGA) and SGA neonates of South Indian women. Placental samples were collected from AGA (n = 40) and SAG (n = 40) neonates. The methylation of IGF-axis genes promoter was analyzed using MS-PCR. IGF2, H19, IGF1, and IGFR1 genes promoter methylation was 2.5, 1.5, 5, and 7.5% lower in SGA compared to AGA, respectively. Co-methylation of IGF-axis genes promoter was 40% and 20% in AGA and SGA, respectively. IGF-axis gene promoter methylation significantly (p < 0.05) influenced the levels of IGFBP3 protein, birth weight, mitotic index, gestational weeks, and IGFR1 and IGFR2 gene expression. IGF-axis genes methylation was lower in SGA than in AGA, and the methylation significantly influenced the IGF-axis components. [ABSTRACT FROM AUTHOR]

Chronic kidney disease (CKD) poses a global health challenge, engendering various physiological and metabolic shifts that significantly impact health and escalate the susceptibility to severe illnesses. This comprehensive review delves into the intricate complexities of CKD, scrutinizing its influence on cellular growth homeostasis, hormonal equilibrium, wasting, malnutrition, and its interconnectedness with inflammation, oxidative stress, and cardiovascular diseases. Exploring the genetic, birth-related, and comorbidity factors associated with CKD, alongside considerations of metabolic disturbances, anemia, and malnutrition, the review elucidates how CKD orchestrates cellular growth control. A pivotal focus lies on the nexus between CKD and insulin resistance, where debates persist regarding its chronological relationship with impaired kidney function. The prevalence of insulin abnormalities in CKD is emphasized, contributing to glucose intolerance and raising questions about its role as a precursor or consequence. Moreover, the review sheds light on disruptions in the growth hormone and insulin-like growth factor axis in CKD, underscoring the heightened vulnerability to illness and mortality in cases of severe growth retardation. Wasting, a prevalent concern affecting up to 75% of end-stage renal disease (ESRD) patients, is analyzed, elucidating the manifestations of cachexia and its impact on appetite, energy expenditure, and protein reserves. Taste disturbances in CKD, affecting sour, umami, and salty tastes, are explored for their implications on food palatability and nutritional status. Independent of age and gender, these taste alterations have the potential to sway dietary choices, further complicating the management of CKD. The intricate interplay between CKD, inflammation, oxidative stress, and cardiovascular diseases is unraveled, emphasizing the profound repercussions on overall health. Additionally, the review extends its analysis to CKD's broader impact on cognitive function, emotional well-being, taste perception, and endothelial dysfunction. Concluding with an emphasis on dietary interventions as crucial components in CKD management, this comprehensive review navigates the multifaceted dimensions of CKD, providing a nuanced understanding essential for developing targeted therapeutic strategies. [ABSTRACT FROM AUTHOR]

Platelet concentrates are used for cell induction and stimulation in tissue repair processes. The aim of the present systematic review and meta-analysis was to compare the biological and cellular properties of advanced platelet-rich fibrin (A-PRF) to those of other platelet concentrates. Searches were conducted on the PubMed/Medline, Scopus, Web of Science, Embase and LILACS databases using a search strategy oriented by the guiding question. A total of 589 records were retrieved. Seven articles of in vitro experimental studies were selected for qualitative data analysis and four were selected for meta-analysis. The release of growth factors, distribution of cells in the fibrin membrane, and cell viability, the fibrin network, and fibroblast migration were investigated. In the final analysis, statistically significant differences were found for the A-PRF group with regard to platelet-derived growth factor, transforming growth factor, epidermal growth factor and vascular endothelial growth factor at all assessment times. A difference was found with regard to bone morphogenetic protein only in the later assessment, and no differences among groups were found with regard to platelet-derived growth factor or insulin-like growth factor. The results of this systematic review and meta-analysis suggest that A-PRF has superior cellular properties and better release of growth factors compared to other platelet concentrates. [ABSTRACT FROM AUTHOR]

We elucidated the molecular mechanism of cancer-associated fibroblast (CAF)-associated gene insulin-like growth factor binding protein-2 (IGFBP2)-induced M2 macrophage polarization in the tumor microenvironment involved in glioma progression. The Cancer Genome Atlas (TCGA) and Chinese Glioma Genome Atlas (CGGA) provided bulk RNA-sequencing datasets, ESTIMATE scores for glioma stromal cells, and overall survival-clinicopathological correlation analyses. TIMER provided CAF abundance in the TCGA glioma-related dataset, differential gene analysis was performed for high- and low-CAF groups, and weighted gene coexpression network analysis identified CAF-related genes. Univariate and multifactorial cyclooxygenase (COX) regression analyses created the CAF risk models single sample gene set enrichment analysis, CIBERSORT, and GSE84465. Mice were implanted with gliomas, and Western blot and RT-quantitative PCR showed IGFBP2 in tumor tissues. Adeno-associated virus (AAV) decreased IGFBP2, flow cytometry measured M1 and M2 macrophage ratios, and immunohistochemistry detected markers. TCGA and CGGA transcriptome data showed malignant gliomas had higher stromal cell scores and worse prognoses. Low- and high-CAF TCGA gliomas were detected, and differential expression, WGCNA, and multifactorial COX identified 132 CAF-related genes and seven high-risk genes (CPQ, EFEMP2, IGFBP2, RAB42, TNFRSF12A, and VASN). Neither CAF risk score, grade, nor 1p/19q affected glioma prognosis. CAF only enriched EFEMP2 and IGFBP2. Gene Expression Profiling Interactive Analysis compared EFEMP2 and IGFBP2 expression in normal brain tissue and gliomas. Low-grade glioma and malignant glioblastoma highly expressed IGFBP2 and EFEMP2. GSEA raised IGFBP2. CIBERSORT linked M2 macrophage infiltration to TCGA glioma immune cell subpopulation IGFBP2 expression. IGFBP2 knockdown stopped mouse glioma and M2 macrophage polarization. CAF plays a procarcinogenic role in glioma, and the CAF-related gene IGFBP2 could promote glioma progression by inducing M2 macrophage polarization. NEW & NOTEWORTHY: The cancer-associated fibroblast (CAF)-related gene insulin-like growth factor binding protein-2 (IGFBP2) is highly expressed in gliomas and is associated with poor prognosis. CAF-related gene IGFBP2 promotes glioma progression by inducing polarization of M2 macrophages. This study provides a new basis for an in-depth investigation of the functional mechanisms of the glioma tumor microenvironment and the search for key genes involved in immune regulation in CAF. [ABSTRACT FROM AUTHOR]

Developmental scientists have adopted numerous biomarkers in their research to better understand the biological underpinnings of development, environmental exposures, and variation in long‐term health. Yet, adoption patterns merit investigation given the substantial resources used to collect, analyse, and train to use biomarkers in research with infants and children. We document trends in use of 90 biomarkers between 2000 and 2020 from approximately 430,000 publications indexed by the Web of Science. We provide a tool for researchers to examine each of these biomarkers individually using a data‐driven approach to estimate the biomarker growth trajectory based on yearly publication number, publication growth rate, number of author affiliations, National Institutes of Health dedicated funding resources, journal impact factor, and years since the first publication. Results indicate that most biomarkers fit a "learning curve" trajectory (i.e., experience rapid growth followed by a plateau), though a small subset decline in use over time. [ABSTRACT FROM AUTHOR]

Objective: This study aimed to compare serum insulin-like growth factor (IGF)-1 levels on cycle day 2 among poor ovarian responders, age-matched normal responders, and high responders undergoing in vitro fertilization (IVF). The investigation sought to understand the potential correlation between IGF-1 levels and ovarian response, with a focus on advanced maternal age and poor ovarian response. Methods: Conducted at the High Institute of Infertility Diagnosis and Assisted Reproductive Technologies in Baghdad, this clinical experiment involved 30 infertile individuals. The primary outcome measures included Cycle Day 2 IGF-1 serum levels, anti-Müllerian hormone (AMH) levels, antral follicle count (AFC), and retrieved oocytes. Secondary outcomes comprised intrauterine pregnancy, live birth, unfavorable pregnancy outcomes, oocyte maturation, and fertilization. Participants were categorized based on antral follicle count: Group 1 (≤3 AFC) and Group 2 (4 to 10 AFC). Results: In participants with usual responses, 72.5% had 4-10 AFC, while poor responders had ≤3 AFC in 27.5% of cases. Poor responders exhibited higher mean ages, lower mean AMH, and higher mean IGF-1 levels. However, poor responders and normal responders showed similar mean FSH levels. Female age positively correlated with FSH and IGF-1, while negatively correlating with AMH. The study also indicated negative correlations between female AMH, FSH, and IGF-1, along with a positive correlation between IGF-1 and FSH. Conclusion: The findings suggest that FSH, AMH, and IGF-1 readings in fertility-assessed women can serve as indicators of ovarian age and reserve. The observed correlations with age imply a diminishing ovarian function. This study contributes valuable insights into the relationship between serum IGF-1 levels, ovarian response, and aging, particularly in the context of poor ovarian responders undergoing IVF. [ABSTRACT FROM AUTHOR]

Background: Chronic uncontrolled hyperglycemia, a precursor to chronic low‐grade inflammation, is a leading cause of coronary artery disease (CAD) due to plaque buildup in type‐1 diabetes (T1D) patients. We evaluated levels of 22 inflammatory markers in cross‐sectional serum samples from 1222 subjects to evaluate their potential as risk factors for CAD in T1D patients. Hypothesis: Circulating levels of markers of inflammation may be the risk factors for incident CAD. Methods: The T1D subjects were divided into two groups: those without CAD (n = 1107) and with CAD (n = 115). Serum levels of proteins were assayed using multiplex immunoassays on a Luminex Platform. Differences between the two groups were made by univariate analysis. Multivariate logistic regression was used to ascertain the potential of proteins as risk factors for CAD. Influence of age, duration of diabetes, sex, hypertension, and dyslipidemia was determined in a stepwise manner. Serum levels of 22 proteins were combined into a composite score using Ridge regression for risk‐based stratification. Results: Mean levels of CRP, IGFBP1, IGFBP2, insulin‐like growth factors binding protein‐6 (IGFBP6), MMP1, SAA, sTNFRI, and sTNFRII were elevated in CAD patients (n = 115) compared to T1D patients without CAD (nCAD, n = 1107). After adjusting for age, duration of diabetes, sex, hypertension, and dyslipidemia, higher levels of sTNFRI (odds ratio [OR] = 2.18, 1.1 × 10−3), sTNFRII (OR = 1.52, 1 × 10−2), and IGFBP6 (OR = 3.62, 1.8 × 10−3) were significantly associated with CAD. The composite score based on Ridge regression, was able to stratify CAD patients into low, medium, and high‐risk groups. Conclusions: The results show activation of the TNF pathway in CAD patients. Evaluating these markers in serum can be a potential tool for identifying high‐risk T1D patients for intensive anti‐inflammatory therapeutic interventions. [ABSTRACT FROM AUTHOR]

Aims Numerous studies have established that resistance training is highly effective in preventing and addressing age-related muscle loss (sarcopenia) by enhancing the physiological function of skeletal muscle tissue. Thus, the objective of this study was to assess the impact of 12 weeks of incremental resistance training on the serum levels of myostatin, follistatin, and insulin-like growth factor-1 (IGF-I) in sedentary elderly men. Materials & Methods Thirty sedentary elderly men voluntarily participated in this semiexperimental study and were randomly assigned to either a control group (15 men) with an average age of 62.1±3.7 years and weight of 85.1±7.7 kg, or a resistance training group (15 men) with an average age of 61.3±1.6 years and weight of 82.3±7.8 kg. The resistance training group undertook a 12-week training protocol, while the control group did not engage in any training program during this time. Blood samples and body composition measurements (using dual X-ray absorptiometry) were taken before the study commenced and 48 hours after the last training session concluded. Serum levels of myostatin, follistatin, and IGF-I were determined using the ELISA method. An independent t-test was employed to establish statistical significance between the groups, utilizing SPSS 21 software. Findings After 12 weeks of resistance training, there was a significant decrease in serum myostatin levels and significant increases in serum follistatin and IGF-I levels in comparison to the control group (p=0.05). Conclusion Incremental resistance training proves to be an effective intervention for preventing sarcopenia in elderly individuals by decreasing serum levels of myostatin and increasing serum levels of follistatin and IGF-I. [ABSTRACT FROM AUTHOR]

In vertebrates, insulin-like growth like factors (IGFs) play an important role in growth and other physiological processes. The GH-IGF axis is considered a valuable tool to monitor fish growth performance. Herein, we report the molecular characterization of igf-1, igf-2, and β-actin transcripts and relative expression of igf-1 and igf-2 in the liver and muscle tissue of cage-reared butter catfish, Ompok bimaculatus, in response to different stocking densities (T1, 15 fingerlings m−3; T2, 25 fingerlings m−3; and T3, 35 fingerlings m−3) over 180 days of culture duration. The length of the partial amplified transcript sequence of Obigf-1, Obigf-2, and Obβ-actin was 325, 438, and 924 bp, respectively. Phylogenetically, Obigf-1 and Obigf-2 were closely clustered with catfishes, viz., Clarias magur, Bagarius yarrelli, and Silurus asotus. The expression of igf-1 was significantly downregulated in the liver at higher densities after 120 days as biomass in the cages increased, while igf-2 expression did not change with the stocking densities over the culture period. Cortisol concentration was significantly elevated in T3 groups post 150 days of the culture period and correlated negatively with the expression of igf-1 (p < 0.05) and igf-2 (p > 0.05). Environmental parameters, pH, TDS, hardness, conductivity, and alkalinity showed a significant positive correlation with hepatic IGF expression. Our study indicates that the liver-derived igf-1 plays a more important role in the regulation of growth in response to culture density in the species studied, and thus, igf-1 can be used effectively as a biomarker for growth. Furthermore, this study will help in planning a proper harvest schedule and optimize the culture practices of O. bimaculatus in an open water cage system. [ABSTRACT FROM AUTHOR]

Simple Summary: Insulin and insulin-like growth factor 1 (IGF1) are metabolic hormones, which are often upregulated to stimulate proliferation in breast cancer. A fasting mimicking diet (FMD) targets insulin signaling pathway downregulation to hamper tumor growth. Genes encoding for the insulin receptors on the cell's surface contain genetic variation between patients, which can affect insulin receptor function and cellular response. Therefore, a group of 113 patients with HER2-negative breast cancer receiving neoadjuvant chemotherapy with or without a fasting mimicking diet were investigated. We found that two IGF1 receptor variants were associated with worse pathological response compared to the reference alleles, out of the 17 interrogated common variants. Additionally, two IGF1 receptor variants could interact negatively within the FMD group regarding radiological response. These results emphasize that genetic variation harbors predictive clinical relevance to optimize and personalize cancer therapy. Aim: We aimed to investigate associations between IGF1R and INSR single nucleotide variants (SNVs) and clinical response in patients with breast cancer treated with neoadjuvant chemotherapy with or without a fasting mimicking diet (FMD) from the DIRECT trial (NCT02126449), since insulin-like growth factor 1 (IGF1) and the insulin pathway are heavily involved in tumor growth and progression. Methods: Germline DNA from 113 patients was tested for 17 systematically selected candidate SNVs in IGF1R and INSR with pathological and radiological response. Results: IGF1R variants A > G (rs3743259) and G > A (rs3743258) are associated with worse pathological response compared to reference alleles p = 0.002, OR = 0.42 (95%CI: 0.24; 0.73); p = 0.0016; OR = 0.40 (95%CI: 0.23; 0.70). INSR T > C (rs1051690) may be associated with worse radiological response p = 0.02, OR = 2.92 (95%CI: 1.16; 7.36), although not significant after Bonferroni correction. Exploratory interaction analysis suggests that IGF1R SNVs rs2684787 and rs2654980 interact negatively with the FMD group regarding radiological response p = 0.036, OR = 5.13 (95%CI: 1.12; 23.63); p = 0.024, OR = 5.71 (95%CI: 1.26; 25.85). Conclusions: The IGF1R variants rs3743259 and rs3743258 are negatively associated with pathological response in this cohort, suggesting potential relevance as a predictive biomarker. Further research is needed to validate these findings and elucidate the underlying mechanisms and interaction with FMD. [ABSTRACT FROM AUTHOR]

Simple Summary: The prognosis of metastatic colorectal cancer patients remains poor despite the increased number of active treatments. This particularly applies to patients with chemorefractory disease. Biomarkers that could help prognostication and management decisions in this setting are lacking. This is the study with the largest panel (n = 182) of circulating cytokines ever assessed in metastatic colorectal cancer. By analyzing 196 chemorefractory colorectal cancer patients with available plasma samples, we showed that high concentrations of IGFBP-1 and/or IGFBP-2 were associated with shorter overall survival. These results are consistent with the extensive literature supporting an association between the IGF pathway and colorectal cancer. Further research is needed to validate our findings in larger independent series, and to elucidate the biological mechanisms underlying the prognostic effect of these cytokines. Circulating cytokines could be optimal biomarkers for prognostication and management decisions in colorectal cancer (CRC). Chemorefractory CRC patients with available plasma samples were included in this study. In the discovery cohort (n = 85), 182 circulating cytokines were tested with a semi-quantitative multiplex assay, and prognostic cytokines were analyzed in the validation cohort (n = 111) by ELISA. Overall survival (OS) was the primary outcome measure, with the false discovery rate (FDR) method (significance level of <0.01) being used to correct for multiple comparisons. Four cytokines were associated with OS in the discovery cohort: insulin-like growth factor-binding protein 1 (IGFBP-1) (HR 2.1 [95%CI: 1.58–2.79], FDR < 0.001), insulin-like growth factor-binding protein 2 (IGFBP-2) (HR 1.65 [95%CI: 1.28–2.13], FDR = 0.006), serum amyloid A (SAA) (HR 1.84 [95%CI: 1.39–2.43], FDR < 0.001), and angiotensin II (HR 1.65 [95%CI: 1.29–2.1], FDR = 0.006). Of these, IGFBP-1 (HR 2.70 [95%CI: 1.56–4.76], FDR = 0.007) and IGFBP-2 (HR 3.33 [95%CI: 1.64–6.67], FDR = 0.008) were confirmed to be independently associated with OS in the validation cohort. Patients with high concentrations of IGFBP-1 and/or IGFBP-2 had a median OS of 3.0 months as compared with 6.9 months for those with low concentrations of both cytokines (HR 2.44 [95%CI: 1.52–4.0], FDR = 0.002) Validation of circulating IGFBP-1 and IGFBP-2 as independent prognostic biomarkers for chemorefractory CRC in larger, independent series is warranted. [ABSTRACT FROM AUTHOR]

Manganese (Mn) is an essential trace element, but insufficient or excessive bodily amounts can induce neurotoxicity. Mn can directly increase neuronal insulin and activate insulin-like growth factor (IGF) receptors. As an important cofactor, Mn regulates signaling pathways involved in various enzymes. The IGF signaling pathway plays a protective role in the neurotoxicity of Mn, reducing apoptosis in neurons and motor deficits by regulating its downstream protein kinase B (Akt), mitogen-activated protein kinase (MAPK), and mammalian target of rapamycin (mTOR). In recent years, some new mechanisms related to neuroinflammation have been shown to also play an important role in Mn-induced neurotoxicity. For example, DNA-sensing receptor cyclic GMP–AMP synthase (cCAS) and its downstream signal efficient interferon gene stimulator (STING), NOD-like receptor family pyrin domain containing 3(NLRP3)-pro-caspase1, cleaves to the active form capase1 (CASP1), nuclear factor κB (NF-κB), sirtuin (SIRT), and Janus kinase (JAK) and signal transducers and activators of the transcription (STAT) signaling pathway. Moreover, autophagy, as an important downstream protein degradation pathway, determines the fate of neurons and is regulated by these upstream signals. Interestingly, the role of autophagy in Mn-induced neurotoxicity is bidirectional. This review summarizes the molecular signaling pathways of Mn-induced neurotoxicity, providing insight for further understanding of the mechanisms of Mn. [ABSTRACT FROM AUTHOR]

Over the last decade, a considerable amount of new data have revealed the beneficial effects of exercise on hippocampal neurogenesis and the maintenance or improvement of cognitive function. Investigations with animal models, as well as human studies, have yielded novel understanding of the mechanisms through which endocrine signaling can stimulate neurogenesis, as well as the effects of exercise on acute and/or chronic levels of these circulating hormones. Considering the effects of aging on the decline of specific endocrine factors that affect brain health, insights in this area of research are particularly important. In this review, we discuss how different forms of exercise influence the peripheral production of specific endocrine factors, with particular emphasis on brainderived neurotrophic factor, growth hormone, insulin-like growth factor-1, ghrelin, estrogen, testosterone, irisin, vascular endothelial growth factor, erythropoietin, and cortisol. We also describe mechanisms through which these endocrine responses to exercise induce cellular changes that increase hippocampal neurogenesis and improve cognitive function. [ABSTRACT FROM AUTHOR]

Background: Observational epidemiological studies revealed that multiple serum biomarkers can be associated with the risk of oral and oropharyngeal cancer (OC/OPC). However, the causal relationship between them remains largely unknown. This study aimed to investigate the causal relationship between potential serum biomarkers and (OC/OPC). Methods: A two-sample Mendelian randomization (MR) approach was performed to assess the causal association of 10 serum biomarkers with the risk of OC / OPC. Summary data on OC/OPC were obtained from a GWAS meta-analysis that included 2497 cases and 2928 controls. The TwoSampleMR package in R was used to perform MR analyzes. Inverse-variance weighted (IVW), Weighted median and MR-Egger methods were used to assess causal effects. Results: Suggestive associations with increased risk of C-reactive protein (CRP) (OR 1.52, 95% CI 1.14 to 2.02), using the IVW method. MR-Egger regression suggested that directional pleiotropy was unlikely to bias the result (P = 0.19). The findings were robust to sensitivity analyzes. The risk of OC/OPC was not associated with serum 25-hydroxyvitamin D, HDL cholesterol, LDL cholesterol, total cholesterol, triglycerides, adiponectin, leptin, HbA1C and Insulin-like growth factor 1 (IGF 1). Conclusions: This study supports that CRP was causally associated with an increased risk of oral and oropharyngeal cancer. [ABSTRACT FROM AUTHOR]

Background: Acremonium terricola is used in the feed of dairy animals to promote growth and control diseases. However, the effects of dietary supplementation with A. terricola on the gut microbial structure of weaning piglets remain poorly understood. Therefore, in this study, we investigated the effects of dietary supplementation with A. terricola culture (ATC) on the growth performance, antioxidant status, immunity, and gut environment of weaning piglets. Sixty piglets were fed a basal diet supplemented with 1 g ATC/kg of basal diet (experimental group). Another 60 piglets did not receive ATC (control group). The intervention lasted for 20 days. Results: The experimental group had higher daily weight gain and feed efficiency than did the control group. Significant increases were noted in the levels of serum insulin (P = 0.0018), insulin-like growth factor (P = 0.0018), triiodothyronine (P = 0.0031), immunoglobulin A (P < 0.0001), immunoglobulin M (P = 0.001), immunoglobulin G (P = 0.0001), and interferon γ (P < 0.0001) in the experimental group compared with the levels in the control group. Furthermore, ATC supplementation significantly reduced (P < 0.05) the relative abundance of Shuttleworthia, Succinivibrio, Roseburia, Ruminococcus, and Paludibacter but increased that of Phascolarctobacterium, Megasphaera, Faecalibacterium, and Prevotella in the experimental group compared with that in the control group. Notably, ATC supplementation significantly increased the relative abundance of Faecalibacterium prausnitzii (P < 0.05), which is involved in anti-inflammatory activities, gut barrier enhancement, and butyrate production. Conclusions: Dietary supplementation with ATC may improve the growth performance, antioxidant status, immunity, and fecal microflora of weaning pigs. [ABSTRACT FROM AUTHOR]

Insulin-like growth factors 2 (IGF2) is an insulin-like growth factor that plays a major role in animal growth, cell proliferation and differentiation, as well as reproduction. IGF2 is well-known to be a candidate gene of growth and reproductive traits in many agricultural animals. Our previous study revealed that the G63A (Chr2: G26541617A) mutation within IGF2 exon 1 showed a significant association with egg numbers (E180d) of Sanhua goose population (p < 0.05). However, little work focus on the correlation between the IGF2 mutations and goose growth traits. In this study, qPCR indicated that the IGF2 mRNA highly expressed in leg muscle, liver, ovary and pituitary gland. Meanwhile, association analysis showed that the G63A mutation was significantly associated with the body weight of first-hatched Zhedong-White geese (BW0, p < 0.05), and strongly significantly associated with the BW2, BW4, BW6, BW8 and BW10 (p < 0.01). The GG homozygous had the lowest BW (from 4 weeks to 10 weeks) than those of AA and AG genotypes (p < 0.01), and the allele A was also positively correlated with the BW of the Zhedong-White goose population. Therefore, the G63A mutation in IGF2 may be an important genetic marker for goose breeding. [ABSTRACT FROM AUTHOR]

Growth is an important trait in aquaculture and the major genes that regulate it are Insulin-like growth factors (IGFs) and IGF binding proteins (IGFBPs). In this study, the full-length coding sequences of IGF2 and IGFBP6 genes in the Indian catfish Clarias magur were cloned and characterized. The full-length cDNA sequences of IGF2 and IGFBP6 were 885 bp (ORF 642 bp) and 928 bp (ORF 600 bp), encoding 213 and 199 amino acids, respectively. Bioinformatics analyses revealed that the magur IGF2 and IGFBP6 proteins are hydrophilic and secretory in nature. Sequence alignment with other teleosts and mammalian orthologues shows conservation of the functional domains. Gene expression analysis in 6 individuals each of high (298 ± 5.0 g) and low (210 ± 6.0 g) growth performing families showed significantly (p < 0.05) higher expression (2.5–3 fold) of IGF2, and lower expression (∼2.5 fold) of IGFBP6 in liver and muscle of fast-growing fish. This study suggests that IGF2 could be playing a major role in the growth regulation of magur. These genes and their expression patterns could be developed into growth-associated markers for magur and other catfishes. [ABSTRACT FROM AUTHOR]

Backgrounds: Nonalcoholic fatty liver disease (NAFLD) exhibits a close association with osteoporosis. This work aims to assess the potential effects of NAFLD on the progression of osteopenia in animal models. Methods: Forty-eight C57BL/6 female mice were randomly divided to wild-type (WT) group and high-fat diet (HFD) group. The corresponding detections were performed after sacrifice at 16, 24 and 32 weeks, respectively. Results: At 16 weeks, an remarkable increase in body weight and lipid aggregation in the hepatocytes of HFD group was observed compared to the WT group, while the bone structure parameters showed no significant difference. At 24 weeks, the levels of TNF-α and IL-6 in NAFLD mice were significantly increased, while the level of osteoprotegerin mRNA in bone tissue was decreased, and the level of receptor activator of nuclear factor Kappa-B ligand mRNA was increased. Meanwhile, the function of osteoclasts was increased, and the bone microstructure parameters showed significant changes. At 32 weeks, in the HFD mice, the mRNA levels of insulin-like growth factor-1 (IGF-1), runt-related transcription factor 2, and osterix mRNA were reduced, while the insulin-like growth factor binding protein-1 (IGFBP-1) level was increased. Simultaneously, the osteoblast function was decreased, and the differences of bone structure parameters were more significant, showing obvious osteoporosis. Conclusions: The bone loss in HFD mice is pronounced as NAFLD progresses, and the changes of the TNF-α, IL-6, IGF-1, and IGFBP-1 levels may play critical roles at the different stages of NAFLD in HFD. Main Points: Bone loss in the HFD mice becomes increasingly apparent with NAFLD progression. The changes of the TNF-α, IL-6, IGF-1, and IGFBP-1 levels are important at the different stages of NAFLD in the HFD mice. [ABSTRACT FROM AUTHOR]

The reasons initiating insulin resistance are not identified. Various metabolic derailments have been characterized. These are the outcome and not the initiation of insulin resistance. In animal models of type 2 diabetes and hypertension, a decreased hormonal stimulation of the synthesis of the cyclic AMP antagonist prostaglandylinositol cyclic phosphate (cyclic PIP) was determined. The resultant imbalance of the action of cyclic AMP and cyclic PIP shifts metabolic regulation to the dominance of catabolism and a decrease in imperative anabolism. This dominance develops gradually since the more cyclic AMP dominates, the more the synthesis of cyclic PIP will be inhibited. Vanishing actions of cyclic PIP are its 10-fold activation of glucose uptake in adipocytes, its inhibition of insulin release from pancreatic β-cells, its inhibition of PKA and its 7-fold activation of protein ser/thr phosphatase. Reduced synthesis of cyclic PIP results from (a) decreased substrate availability, (b) long-time elevated cyclic AMP levels resulting from stress overloads and (c) aging and the gradual decrease in the synthesis of hormones which likely maintain mechanisms that stimulate cyclic PIP synthesis. The need is to discover which hormones, such as growth hormone, insulin-like growth factor-1, dehydroepiandrosterone, and testosterone, are involved in maintaining the stimulation of cyclic PIP synthesis. [ABSTRACT FROM AUTHOR]

Since our discovery in 2006 that acromegaly is associated with an increased risk of vertebral fractures, many authors have confirmed this finding in both cross-sectional and prospective studies. Due to the high epidemiological and clinical impact of this newly discovered comorbidity of acromegaly, this topic has progressively become more important and prominent over the years, and the pertinent literature has been enriched by new findings on the pathophysiology and treatment. The aim of this narrative review was to discuss these novel findings, integrating them with the seminal observations, in order to give the reader an updated view of how the field of acromegaly and bone is developing, from strong clinical observations to a mechanistic understanding and possible prevention and treatment. [ABSTRACT FROM AUTHOR]

Background: Optimizing patient selection for neoadjuvant chemotherapy in patients with breast cancer remains an unmet clinical need. Quantitative features from medical imaging were reported to be predictive of treatment responses. However, the biologic meaning of these latent features is poorly understood, preventing the clinical use of such noninvasive imaging markers. The study aimed to develop a deep learning signature (DLS) from pretreatment magnetic resonance imaging (MRI) for predicting responses to neoadjuvant chemotherapy in patients with breast cancer and to further investigate the biologic meaning of the DLS by identifying its underlying pathways using paired MRI and proteomic sequencing data. Methods: MRI‐based DLS was constructed (radiogenomic training dataset, n = 105) and validated (radiogenomic validation dataset, n = 26) for the prediction of pathologic complete response (pCR) to neoadjuvant chemotherapy. Proteomic sequencing revealed biological functions facilitating pCR (n = 139). Their associations with DLS were uncovered by radiogenomic analysis. Results: The DLS achieved a prediction accuracy of 0.923 with an AUC of 0.958, higher than the performance of the model trained by transfer learning. Cellular membrane formation, endocytosis, insulin‐like growth factor binding, protein localization to membranes, and cytoskeleton‐dependent trafficking were differentially regulated in patients showing pCR. Oncogenic signaling pathways, features correlated with human phenotypes, and features correlated with general biological processes were significantly correlated with DLS in both training and validation dataset (p.adj < 0.05). Conclusions: Our study offers a biologically interpretable DLS for the prediction of pCR to neoadjuvant chemotherapy in patients with breast cancer, which may guide personalized medication. [ABSTRACT FROM AUTHOR]

Context: Acromegaly is a rare, chronic, debilitating disorder caused by prolonged hypersecretion of growth hormone (GH) and overproduction of insulin-like growth factor I (IGF-I). Medical therapies, including the somatostatin receptor ligand (SRL) pasireotide, are frequently used to restore biochemical control. Objective: As patients often receive therapy over prolonged periods, long-term data from real-life settings are needed. Methods: A retrospective analysis was performed using a prospectively maintained database of all patients with acromegaly from our primary care center who were enrolled in clinical studies with pasireotide (first visit November 2008). The main outcome measures were safety and biochemical control (age-adjusted IGF-I ≤ upper limit of normal). Results: Patients (n = 50) entered 4 parental studies and 30 continued in the rollover; at data cutoff (June 2022), 27 were still receiving pasireotide. Overall, median (range) exposure was 58 (3-137) months. Normal IGF-I was achieved in 54%, and acromegaly symptoms and quality of life were improved with treatment. No predictors of pasireotide response were identified; however, controlled patients had smaller tumors and lower GH at baseline. Tumor volume reduction occurred in 63% of evaluable patients (n = 10/16). Most patients presented hyperglycemic events, including 63.2% of patients with normal glucose before treatment. Older patients and those with higher IGF-I, glucose, and HbA1c at baseline had higher glucose and HbA1c during pasireotide treatment. Conclusion: Pasireotide provided clinical benefit and was well tolerated for more than 11 years of treatment in acromegaly patients, most of whom were resistant to first-generation SRLs. [ABSTRACT FROM AUTHOR]

Objective: To analyze the relation between alterations in the growth hormone (GH)/insulin-like growth factor 1 (IGF-1) axis during the first 6 months of life and weight in children born in the lower-middle São Francisco region. Methods: This is an analytical cohort and exploratory. Thirty children, were formed two groups, one of low birth weight children (LBW, n = 15) and another of normal weight (NBW = 15) were initially identified in a hospital and reapproached at 3 and 6 months of age. Birth weight and alterations in GH/IGF-1 curves were measured at birth and the third and sixth months of life. Results: Weight gain during the 6 months of follow-up in newborns with a low birth weight was greater compared to newborns with a normal birth weight. All children who were born with a low birth weight had an altered GH/IGF-1 curve at birth (p = 0.002). Most newborns with a low birth weight maintained the alteration in the GH/IGF-1 curve at the third month of life (p = 0.027). Regarding the GH/IGF-1 curve at the sixth month, alteration persisted in greater proportion among children with a low birth weight. Conclusions: Alterations in insulin resistance markers, demonstrated by increased GH without a proportional increase in IGF-1, were observed to be significant in children with a low birth weight with greater adiposity in this group which may increase the risk of metabolic diseases in later life. [ABSTRACT FROM AUTHOR]

Pregnancy-associated plasma protein-A (PAPP-A) was first identified in the early 1970s as a placental protein of unknown function, present at high concentrations in the circulation of pregnant women. In the mid-to-late 1990s, PAPP-A was discovered to be a metzincin metalloproteinase, expressed by many nonplacental cells, that regulates local insulin-like growth factor (IGF) activity through cleavage of high-affinity IGF binding proteins (IGFBPs), in particular IGFBP-4. With PAPP-A as a cell surface–associated enzyme, the reduced affinity of the cleavage fragments results in increased IGF available to bind and activate IGF receptors in the pericellular environment. This proteolytic regulation of IGF activity is important, since the IGFs promote proliferation, differentiation, migration, and survival in various normal and cancer cells. Thus, there has been a steady growth in investigation of PAPP-A structure and function outside of pregnancy. This review provides historical perspective on the discovery of PAPP-A and its structure and cellular function, highlights key studies of the first 50 years in PAPP-A research, and introduces new findings from recent years. [ABSTRACT FROM AUTHOR]

Insulin-like growth factor-binding protein (IGFBP)-2 regulates the bioactivity of the anabolic hormone's insulin-like growth factors, which are decreased in sepsis and contribute to the catabolic status of severely ill patients. The circulating levels of IGFBP-2 in critical illness have been rarely studied; therefore, we evaluated IGFBP-2 plasma levels in patients with systemic inflammatory response syndrome (SIRS) or sepsis as well as healthy controls. Our analysis of 157 SIRS/sepsis patients revealed higher plasma IGFBP-2 levels compared to 22 healthy controls. Plasma IGFBP-2 levels correlated positively with procalcitonin but not with C-reactive protein, interleukin-6, or the leukocyte count. Septic shock patients exhibited higher IGFBP-2 levels than those with SIRS. Bacterial or SARS-CoV-2 infection did not influence plasma IGFBP-2 levels. There was no difference in the IGFBP-2 levels between ventilated and non-ventilated SIRS/sepsis patients, and vasopressor therapy did not alter these levels. Dialysis patients had elevated plasma IGFBP-2 levels. Survivors had lower plasma IGFBP-2 levels than non-survivors. In conclusion, our study indicates that plasma IGFBP-2 levels are associated with disease severity, renal failure, and mortality in SIRS/sepsis patients. [ABSTRACT FROM AUTHOR]

Purpose: There is a documented association between cervical cancer and metabolic syndrome. In this study, we determined the association between lipids, insulin-like growth factor binding protein-3 (IGFBP-3) and treatment outcomes for cervical lesions at Mbarara Regional Referral Hospital (MRRH) in south western Uganda. Patients and Methods: In this prospective cohort study, we recruited 94 cases and 94 controls at the cervical cancer clinic of MRRH, and followed them for 12 months. Cases were confirmed with cytology and/or histology. With consent, we collected demographic data and measured lipids and IGFBP-3 both at baseline and after 12 months. The lipid profile was measured using a Cobas 6000 Chemistry Analyzer, whereas IGFBP-3 was measured using a MAGLUMI fully automated chemiluminescence immunoassay analyzer. Abnormal values for lipids were defined using WHO recommended cut-offs. IGFBP-3 concentrations were divided into two categories of low concentration (< 3.29 μg/mL) and raised concentration (≥ 3.29 μg/mL). Statistical analyses were conducted in STATA version 17 using logistic regression analysis. A p-value of < 0.05 was taken to be statistically significant. Results: The average (mean ± SD) age of our participants was 38.7± 8.2 years for controls and 34.5± 7.8 years for cases. The average serum IGFBP-3 concentration was 3.769± 1.098 μg/mL among cases with cleared lesions and 3.505± 0.979 μg/mL among cases whose lesions persisted. A serum IGFBP-3 concentration of less than 3.291 μg/mL was likely to be associated with clearance of cervical lesions (AOR 1.65, p=0.67), although this was not statistically significant. A serum triglyceride concentration of 35– 135 mg/dL was also likely to be associated with clearance of cervical lesions (AOR 2.41, p=0.46), although this was also not statistically significant. Conclusion: Although not statistically significant, reduced serum concentrations of IGFBP-3 and triglyceride may be associated with clearance of cervical lesions. Lipid management may be of benefit in the treatment of cervical lesions. [ABSTRACT FROM AUTHOR]

Dietary restriction is a frequent strategy for weight loss, but adherence is difficult and returning to poor dietary habits can result in more weight gain than that previously lost. How weight loss due to unrestricted intake of a healthy diet affects the response to resumption of poor dietary habits is less studied. Moreover, whether this response differs between the sexes and if the insulin-like growth factor (IGF) system, sex dependent and involved in metabolic control, participates is unknown. Mice received rodent chow (6% Kcal from fat) or a high-fat diet (HFD, 62% Kcal from fat) for 4 months, chow for 3 months plus 1 month of HFD, or HFD for 2 months, chow for 1 month then HFD for 1 month. Males and females gained weight on HFD and lost weight when returned to chow at different rates (p < 0.001), but weight gain after resumption of HFD intake was not affected by previous weight loss in either sex. Glucose metabolism was more affected by HFD, as well as the re-exposure to HFD after weight loss, in males. This was associated with increases in hypothalamic mRNA levels of IGF2 (p < 0.01) and IGF binding protein (IGFBP) 2 (p < 0.05), factors involved in glucose metabolism, again only in males. Likewise, IGF2 increased IGFBP2 mRNA levels only in hypothalamic astrocytes from males (p < 0.05). In conclusion, the metabolic responses to dietary changes were less severe and more delayed in females and the IGF system might be involved in some of the sex specific observations. [ABSTRACT FROM AUTHOR]

Osteoarthritis (OA) is defined as a degenerative joint disease that can affect all tissues of the joint, including the articular cartilage, subchondral bone, ligaments capsule, and synovial membrane. The conventional nonoperative treatments are ineffective for cartilage repair and induce only symptomatic relief. Platelet-rich plasma (PRP) is a platelet concentrate derived from autologous whole blood with a high concentration of platelets, which can exert anti-inflammatory and regenerative effects by releasing multiple growth factors and cytokines. Recent studies have shown that PRP exhibits clinical benefits in patients with OA. However, high operational and equipment requirements greatly limit the application of PRP to OA treatment. Past studies have indicated that high-concentration PRP growth factors and cytokines may be applied as a commercial replacement for PRP. We reviewed the relevant articles to summarize the feasibility and mechanisms of PRP-based growth factors in OA. The available evidence suggests that transforming growth factor-α and β, platelet-derived growth factors, epidermal growth factor, insulin-like growth factor-1, and connective tissue growth factors might benefit OA, while vascular endothelial growth factor, tumor necrosis factor-α, angiopoietin-1, and stromal cell derived factor-1α might induce negative effects on OA. The effects of fibroblast growth factor, hepatocyte growth factor, platelet factor 4, and keratinocyte growth factor on OA remain uncertain. Thus, it can be concluded that not all cytokines released by PRP are beneficial, although the therapeutic action of PRP has a valuable potential to improve. [ABSTRACT FROM AUTHOR]

Standard treatment for acromegaly focuses on the achievement of target absolute levels of growth hormone (GH) and insulin-like growth factor (IGF-I). The appropriateness of these targets when measured using modern assay methods is not well defined. This paper reviews biochemical status assessed using methods available at the time and associated clinical outcomes. GH measurements were shown to provide an indication of changes in tumor size, and failure of GH suppression after glucose stimulation is associated with tumor recurrence. IGF-I levels were more closely associated with changes in symptoms and signs. Reduced GH and IGF-I concentrations were shown to be associated with increased longevity, although the degree of increase has only been analyzed for GH. Lowering of GH and IGF-I has consistently been associated with improved outcomes; however, absolute levels reported in previous studies were based on results from methods and reference ranges that are now obsolete. Applying previously described absolute thresholds as targets (e.g. "normal" IGF-I level) when using current methods is best applied to those with active acromegaly symptoms who could benefit from further lowering of biochemical markers. In asymptomatic individuals with mild IGF-I or GH elevations, targeting biochemical "normalization" would result in the need for combination pharmacotherapy in many patients without proven benefit. Measurement of both GH and IGF-I remains an essential component of diagnosis and monitoring the effectiveness of treatment in acromegaly; however, treatment goals based only on previously identified absolute thresholds are not appropriate without taking into account the assay and reference ranges being employed. Treatment goals should be individualized considering biochemical improvement from an untreated baseline, symptoms of disease, risks, burdens and costs of complex treatment regimens, comorbidities, and quality of life. [ABSTRACT FROM AUTHOR]

Metastasis has emerged as a major impediment to achieve successful therapeutic outcomes in hepatocellular carcinoma (HCC). Nonetheless, the intricate molecular mechanisms governing the progression of HCC remain elusive. Herein, we present evidence highlighting the influence exerted by insulin-like growth factor-binding protein 2 (IGFBP2) as a potent oncogene driving the malignant phenotype. Our investigation reveals a marked elevation of IGFBP2 expression in primary tumors, concomitant with the presence of mesenchymal biomarkers in HCC. Through in vitro and in vivo experimentation, we demonstrate that the overexpression of IGFBP2 expedites the progression of epithelial-mesenchymal transition (EMT) and facilitates the metastatic potential of HCC cells, chiefly mediated by the Wnt/β-catenin signaling pathway. Notably, knockdown of IGFBP2 significantly decreased the expression of total and nuclear β-catenin, N-cadherin and vimentin in the treatment of the specific activator of Wnt/β-catenin CHIR-99021. Collectively, our findings identify IGFBP2 as a pivotal regulator within the HCC EMT axis, whereby its overexpression confers the distinctly aggressive clinical features characteristic of the disease. [ABSTRACT FROM AUTHOR]

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-β1, 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-β1/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-β1 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-β1/ VEGF, while IGFBP-3 in umbilical blood was linked to IGF-1/TGF-β1. 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 TGFβ1 in the IGF/PI3K/Akt, TGF-β1/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. [ABSTRACT FROM AUTHOR]

The growth hormone (GH)-insulin-like growth factor-1 (IGF1) signaling pathway emerged in recent years as a key determinant of aging and longevity. Disruption of this network in different animal species, including flies, nematodes and mouse, was consistently associated with an extended lifespan. Epidemiological analyses have shown that patients with Laron syndrome (LS), the best-characterized disease under the umbrella of the congenital IGF1 deficiencies, seem to be protected from cancer. While aging and cancer, as a rule, are considered diametrically opposite processes, modern lines of evidence reinforce the notion that aging and cancer might, as a matter of fact, be regarded as divergent manifestations of identical biochemical and cellular underlying processes. While the effect of individual mutations on lifespan and health span is very difficult to assess, genome-wide screenings identified a number of differentially represented aging- and longevity-associated genes in patients with LS. The present review summarizes recent data that emerged from comprehensive analyses of LS patients and portrays a number of previously unrecognized targets for GH-IGF1 action. Our article sheds light on complex aging and longevity processes, with a particular emphasis on the role of the GH-IGF1 network in these mechanisms. [ABSTRACT FROM AUTHOR]

Previous studies have reported that collagen tripeptide (CTP) derived from collagen hydrolysate has various beneficial effects on health by protecting against skin aging and improving bone formation and cartilage regeneration. Collagen-Tripep20TM (CTP20), which is a low-molecular-weight CTP derived from fish skin, contains a bioactive CTP, Gly-Pro-Hyp >3.2% with a tripeptide content >20%. Herein, we investigated the osteogenic effects and mechanisms of CTP20 (<500 Da) on MG-63 osteoblast-like cells and SW1353 chondrocytes. And we measured promoting ratio of the longitudinal bone growth in childhood rats. First, CTP20 at 100 μg/mL elevated the proliferation (15.0% and 28.2%), alkaline phosphatase activity (29.3% and 32.0%), collagen synthesis (1.25- and 1.14-fold), and calcium deposition (1.18- and 1.15-fold) in MG-63 cells and SW1353, respectively. In addition, we found that CTP20 could promote the longitudinal growth and height of the growth plate of the tibia in childhood rats. CTP20 enhanced the protein expression of insulin-like growth factor-1 (IGF-1) in MG-63 and SW1353 cells, and in the growth plate of childhood rats, along with Janus Kinase 2, and signal transducer and activator of transcription 5 activation in MG-63 and SW1353 cells. CTP20 also elevated the expression levels of bone morphogenetic proteins (BMPs) in MG-63 and SW1353 cells and in the growth plates of childhood rats. These results indicate that CTP20 may promote the endochondral ossification and longitudinal bone growth, through enhancing of IGF-1 and BMPs. (Clinical Trial Registration number: smecae 19-09-01). [ABSTRACT FROM AUTHOR]

This study aimed to evaluate the effects of in ovo injection of soy isoflavones (ISF) on hatchability, body weight, antioxidant status and intestinal development of newly hatched broiler chicks. One hundred and eighty fertile eggs were divided as follows: the control group, 3 mg/egg ISF (low dose) and 6 mg/egg ISF (high dose) on the 18th day of incubation. The results demonstrated that in ovo inclusion of 6 mg of ISF significantly increased hatchability and hatch weight. Both doses of ISF inclusion elevated the serum glutathione peroxidase and slightly decreased malondialdehyde compared to the control group. The high dose of ISF brings higher villus height and a higher villus/crypt ratio in chicks. Moreover, the mRNA levels of tumour necrosis factor‐ α and interferon‐gamma in the spleen were significantly decreased. The ISF treatments showed an improvement in intestinal enzyme expression levels of sucrose isomaltase and mucin 2 as well as tight junction protein (TJ) mRNA expression of claudin‐1 at high doses of ISF (p < 0.05) when compared with the other groups. Furthermore, the mRNA level of IGF‐1 was increased in the high doses of ISF compared to the control. Overall, these findings indicate that in ovo administration of ISF on the 18th day of incubation enhances hatchability, antioxidant status and intestinal morphometrics in hatched chicks and modulates the expression of proinflammatory cytokines, TJs and insulin‐like growth factor. In addition, the sustainability of antioxidants and other positive effects of ISF may increase chick viability and growth performance. [ABSTRACT FROM AUTHOR]

The relationship between intake of dietary supplements and biomarkers such as insulin and insulin-like growth factor has not been well explored. The primary aim of this cross-sectional study was to investigate the associations between supplement intake and biological and lifestyle factors. We hypothesized that dietary supplement intake was associated with healthier lifestyle behaviors. College students attending a Southeast university were recruited between January 2018 and April 2019. Blood samples were collected to measure insulin, insulin-like growth factor 1 (IGF-1) and alanine aminotransferase (ALT). Statistical tests employed were linear regression and analysis of variance. Ninety-eight participants completed the study and 91% reported taking at least one supplement, while 5.1% reported taking 9+ supplements once per week. There were no differences in levels of insulin, IGF-1 and ALT by levels of dietary supplement intake. Although there were no differences in HEI-2015 score among the groups, those who consumed five or more supplements met a higher percentage of the recommended intake for fruits, performed aerobic exercise for longer duration, and had lower body fat percentage compared to participants who consumed two or less supplements at least once per week. These findings are consistent with previous studies and suggest that dietary supplement intake is highly prevalent in college students, and it may be related to healthy lifestyle behaviors. Future studies should employ mixed methodology to examine reasons by which college students consume dietary supplements and to assess perceived and direct health benefits associated with consumption. [ABSTRACT FROM AUTHOR]

Hyperosmolarity of the ocular surface triggers inflammation and pathological damage in dry eye disease (DED). In addition to a reduction in quality of life, DED causes vision loss and when severe, blindness. Mitochondrial dysfunction occurs as a consequence of hyperosmolar stress. We have previously reported on a role for the insulin-like growth factor binding protein-3 (IGFBP-3) in the regulation of mitochondrial ultrastructure and metabolism in mucosal surface epithelial cells; however, this appears to be context-specific. Due to the finding that IGFBP-3 expression is decreased in response to hyperosmolar stress in vitro and in an animal model of DED, we next sought to determine whether the hyperosmolar stress– mediated decrease in IGFBP-3 alters mitophagy, a key mitochondrial quality control mechanism. Here we show that hyperosmolar stress induces mitophagy through differential regulation of BNIP3L/NIX and PINK1-mediated pathways. In corneal epithelial cells, this was independent of p62. The addition of exogenous IGFBP-3 abrogated the increase in mitophagy. This occurred through regulation of mTOR, highlighting the existence of a new IGFBP-3–mTOR signaling pathway. Together, these findings support a novel role for IGFBP-3 in mediating mitochondrial quality control in DED and have broad implications for epithelial tissues subject to hyperosmolar stress and other mitochondrial diseases. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the effect of surgical intervention on serum insulin-like growth factor 1 levels in patients with obstructive sleep apnoea. Methods: A prospective study was conducted in a tertiary care hospital of adult patients with obstructive sleep apnoea for whom continuous positive airway pressure therapy failed or was refused. All patients underwent polysomnography and serum insulin-like growth factor 1 evaluation pre-operatively and at three months post-operatively. The site of surgery was determined using Müller's manoeuvre and ApneaGraph AG 200. Results: Fifteen patients were included with a mean age of 38 years: 11 males and 4 females. The mean pre-operative Apnoea–Hypopnoea Index using polysomnography was 53.7 events per hour, and the mean post-operative Apnoea–Hypopnoea Index at three months was 15.3 events per hour (p = 0.0001). The mean pre-operative serum insulin-like growth factor 1 was 160.2 μg/l, while the mean post-operative value was 236.98 μg/l (p = 0.005). Conclusion: In adult patients with obstructive sleep apnoea for whom continuous positive airway pressure therapy fails, site-specific surgical intervention to treat the obstruction leads to an increase in serum insulin-like growth factor 1 levels. [ABSTRACT FROM AUTHOR]

The paper aimed to explore the mechanism by which high mobility group box-1 and nicotinamide adenine dinucleotide phosphate oxidase-derived reactive oxygen species enhance each other's influence on the amplitude of electroretinogram and the permeability of the vitreous. According to the purpose of the experiment, the experimental rats were separated into a control group, a diabetes group and a Shenling Baizhu powder group. The messenger ribonucleic acid expression of microRNA-23 and microRNA-27a in rat muscle tissue was quantitatively analyzed by real-time quantitative polymerase chain reaction. The contractility of rat soleus skeletal muscle was analyzed by electrical stimulation program. Western blot analysis of rat muscle growth protein synthesis and the expression of myostatin signaling pathway was carried out. The expression of renal fibrosis-related albumin was tested by Western blot. The messenger ribonucleic acid expression of microRNA-23, 27a in the diabetic group was lower than control group (p<0.05), and the expression in the Shenling Baizhu powder group was higher than diabetic group (p<0.05). Compared with the control group, the diabetic group had lower body weight (p<0.05), and raised blood glucose concentration and diabetes volume (p<0.05). The ratio of phosphorylated protein kinase B/protein kinase B and phospho forkhead box protein O1/forkhead box protein O1 protein expression in the Shenling Baizhu powder group was higher than diabetic group (p<0.05), while the phosphatase and tensin homolog protein expression was lower (p<0.05). The protein expression of myostatin, FBXO32 and TRIM63 in the diabetes group was higher than control group (p<0.05), and the expression in the Shenling Baizhu powder group was lower than diabetes group (p<0.05). Compared with the control group, the protein expression of transforming growth factor-beta, suppressor of mothers against decapentaplegic 2/3, alpha-smooth muscle actin, collagen-1a and fibronectin was higher in the diabetes group (p<0.05), and the expression in the Shenling Baizhu powder group was lower than diabetes group (p<0.05). Shenling Baizhu powder can improve diabetes-induced sarcopenia by up-regulating microRNA expression, activating the insulin-like growth factor 1/phosphoinositide 3-kinases/ protein kinase B signaling pathway and inhibiting the myostatin cascade. [ABSTRACT FROM AUTHOR]

Tendon injury healing is a complex process that involves the participation of a significant number of molecules and cells, including growth factors molecules in a key role. Numerous studies have demonstrated the function of growth factors in tendon healing, and the recent emergence of EV has also provided a new visual field for promoting tendon healing. This review examines the tendon structure, growth, and development, as well as the physiological process of its healing after injury. The review assesses the role of six substances in tendon healing: insulin‐like growth factor‐I (IGF‐I), transforming growth factor β (TGFβ), vascular endothelial growth factor (VEGF), platelet‐derived growth factor (PDGF), basic fibroblast growth factor (bFGF), and EV. Different growth factors are active at various stages of healing and exhibit separate physiological activities. IGF‐1 is expressed immediately after injury and stimulates the mitosis of various cells while suppressing the response to inflammation. VEGF, which is also active immediately after injury, accelerates local metabolism by promoting vascular network formation and positively impacts the activities of other growth factors. However, VEGF's protracted action could be harmful to tendon healing. PDGF, the earliest discovered cytokine to influence tendon healing, has a powerful cell chemotaxis and promotes cell proliferation, but it can equally accelerate the response to inflammation and relieve local adhesions. Also useful for relieving tendon adhesion is TGF‐ β, which is active almost during the entire phase of tendon healing. As a powerful active substance, in addition to its participation in the field of cardiovascular and cerebrovascular vessels, tumour and chronic wounds, TGF‐ β reportedly plays a role in promoting cell proliferation, activating growth factors, and inhibiting inflammatory response during tendon healing. [ABSTRACT FROM AUTHOR]

Context Growth hormone (GH) replacement therapy improves longitudinal growth and adult height in children with GH deficiency (GHD). GH stimulates insulin-like growth factor (IGF)-I release, the biomarker used for monitoring GH activity during treatment. Objective This study aims to provide model-based insights into the dose–IGF-I responses of once-weekly somapacitan, a novel long-acting GH, compared with daily GH in children with GHD. Methods Analyses included dosing information and 1473 pharmacokinetic samples from 210 somapacitan-treated pediatric patients with GHD across 3 trials, including phase 1 (NCT01973244), phase 2 (NCT02616562; REAL 3), and phase 3 (NCT03811535; REAL 4), as well as 1381 IGF-I samples from 186 patients with GHD treated with somapacitan in REAL 3 and REAL 4. Pharmacokinetic/pharmacodynamic modeling to characterize somapacitan dose–IGF-I response and predict the response to dosing day changes. Results Relationships were established between somapacitan dose, exposure, change from baseline IGF-I SD score (SDS), and height velocity (HV). A linear model permitted the development of a tool to calculate estimated average weekly IGF-I exposure from a single IGF-I sample obtained at any time within the somapacitan dosing interval at steady state. In practice, the use of this tool requires knowledge of somapacitan injection timing relative to IGF-I sample collection timing. IGF-I SDS simulations support flexible dosing day changes while maintaining at least 4 days between doses. Conclusion We characterized the dose–IGF-I response of somapacitan in children with GHD. To support physicians in IGF-I monitoring, we present a practical guide about expected weekly average IGF-I concentrations in these patients and provide insights on dosing day flexibility. [ABSTRACT FROM AUTHOR]