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The cation-independent mannose 6-phosphate receptor (CI-MPR) is clinically significant in the treatment of patients with lysosomal storage diseases because it functions in the biogenesis of lysosomes by transporting mannose 6-phosphate (M6P)-containing lysosomal enzymes to endosomal compartments. CI-MPR is multifunctional and modulates embryonic growth and fetal size by downregulating circulating levels of the peptide hormone insulin-like growth factor 2 (IGF2). The extracellular region of CI-MPR comprises 15 homologous domains with binding sites for M6P-containing ligands located in domains 3, 5, 9, and 15, whereas IGF2 interacts with residues in domain 11. How a particular ligand affects the receptor's conformation or its ability to bind other ligands remains poorly understood. To address these questions, we purified a soluble form of the receptor from newborn calf serum, carried out glycoproteomics to define the N-glycans at its 19 potential glycosylation sites, probed its ability to bind lysosomal enzymes in the presence and absence of IGF2 using surface plasmon resonance, and assessed its conformation in the presence and absence of IGF2 by negative-staining electron microscopy and hydroxyl radical protein footprinting studies. Together, our findings support the hypothesis that IGF2 acts as an allosteric inhibitor of lysosomal enzyme binding by inducing global conformational changes of CI-MPR.

Simple Summary: Insulin-like peptides are known to be crucial endocrine hormones that influence various physiological processes, including growth and reproduction in insects. However, the specific roles of insulin-like peptides in the reproduction of natural enemy insects remain to be known. Coccinella septempunctata is an effective biological control agent and it is of great biocontrol significance to study the functions of insulin-like peptide genes in female reproduction of this natural predator. In this study, we cloned two insulin-like peptide genes and analyzed their functions in female C. septempunctata. It was found that silencing these insulin-like peptide genes resulted in significant down-regulation of ovarian development-related genes, leading to a prolonged pre-oviposition period, decreased fecundity, and reduced hatching rates of female C. septempunctata. These findings confirm the regulatory functions of these insulin-like peptide genes in female C. septempunctata reproduction and enhance our understanding of peptide hormones in natural enemy insects, contributing to improved biological pest control strategies. Insulin-like peptides (ILPs) are important peptide hormones in insects, particularly involved in regulating physiological processes such as growth, development, and reproduction. However, the specific roles of ILPs in the reproduction of natural enemy insects remain unknown. In this study, two ILP genes, CsILP1 and CsILP2, were cloned and their functions were analyzed in female Coccinella septempunctata L. (Coleoptera: Coccinellidae). The open reading frames (ORFs) of CsILP1 and CsILP2 were 384 bp and 357 bp, respectively. The expression of CsILP1 increased on the 6th day after eclosion, reaching its peak on the 12th day, while CsILP2 levels showed a significant increase on the 6th day and then stabilized. In different tissues, CsILP1 was highly expressed in ovaries, while CsILP2 predominated in elytra. Injection of dsRNA targeting CsILP1 and CsILP2 resulted in the down-regulation of insulin pathway genes. The relative expression of ovarian development-related genes Vasa, G2/M, and Vg was reduced by 82.50%, 89.55%. and 96.98% in dsCsILP1-treated females, and by 42.55%, 91.36%, and 55.63% in dsCsILP2-treated females. Furthermore, substantial decreases in 14-day fecundity were observed, with reductions of 89.99% for dsCsILP1 and 83.45% for dsCsILP2. These results confirm the regulatory functions of CsILP1 and CsILP2 in female C. septempunctata reproduction. [ABSTRACT FROM AUTHOR]

Insulin‐like peptides (ILPs) act as crucial reproductive neuropeptides in insects, regulating insect reproduction through the insulin signaling pathway (ISP). Our previous studies have found that the sublethal concentrations (LC1 and LC10) of lambda‐cyhalothrin (λCy) could induce severe reproductive toxicity in the lacewing, Chrysoperla sinica (Tjeder), but the toxicological mechanism remains unclear. This study discovered that λCy could inhibit CsILP transcription, leading to a decrease in insulin content and downregulation of C. sinica insulin receptor (CsInR) and C. sinica forkhead box O (CsFOXO) expression in ISP. Interference with CsILP expression resulted in downregulation of C. sinica vitellogenin (CsVg) and decreasing fecundity, while exogenous injection of bovine insulin promoted upregulation of CsVg expression and facilitated reproduction in female adults of C. sinica. Meanwhile, interference with FOXO of ILP downstream transcription factor could lead to downregulation of CsVg, hindering ovarian development and resulting in a decrease in egg production. However, exogenous injection of bovine insulin could remedy the effects caused by FOXO interference. In addition, ILP mediates juvenile hormone and 20‐hydroxyecdysone biosynthesis by acting on their synthetic regulatory enzymes and influences the signal transduction of the 2 reproductive endocrine hormones, thereby regulating the reproductive endocrine environment in C. sinica. In conclusion, λCy inhibits CsILP expression, leading to disorder of ISP, leading to the reduced fecundity of C. sinica. [ABSTRACT FROM AUTHOR]

Simple Summary: This study investigated the influence of exendin-4, a glucagon-like peptide-1 receptor (GLP-1R) agonist, on fall webworm Hyphantria cunea larvae. We found that exendin-4 induced growth arrest by regulating sugar metabolism, affecting digestive enzyme activities, and altering metabolite profiles. Specifically, it decreased glucose and trehalose levels while increasing the glycogen content, indicating a regulatory effect on blood sugar. Exendin-4 also promoted glycolysis and reduced ATP levels, potentially through the activation of AMPK. These findings enhance our understanding of the physiological effects of GLP-1R agonists in insects and could inform pest management strategies. Insects' growth and development are highly dependent on energy supply, with sugar metabolism playing a pivotal role in maintaining homeostasis and regulating physiological processes. The present study investigated the effects of exendin-4, a glucagon-like peptide-1 receptor (GLP-1R) agonist, on the growth, development, glycolysis, and energy metabolism of fourth-instar larvae of the fall webworm, Hyphantria cunea. We determined the impact of exendin-4 on larval growth and nutritional indices, analyzed the responses of glycolytic and metabolic pathways, and revealed the underlying regulatory mechanisms. Exendin-4 treatment significantly decreased growth and nutritional indices, influenced the activity of digestive enzymes, and induced changes in metabolite profiles, particularly affecting energy substance metabolism. We observed an increase in the glycogen content and a decrease in glucose and trehalose levels in the hemolymph, suggesting a regulatory effect on blood sugar homeostasis. Furthermore, exendin-4 promoted glycolysis by enhancing the activities and expressions of key glycolytic enzymes, leading to an increase in pyruvate production. This was accompanied by a reduction in ATP levels and the activation of AMP-activated protein kinase (AMPK), which may underlie the growth arrest in larvae. Our findings provide novel insights into the effects of exendin-4 on insect responses from an energy metabolism perspective and may contribute to the development of GLP-1R agonists for pest management. [ABSTRACT FROM AUTHOR]

Sea anemone venom, abundant in protein and peptide toxins, serves primarily for predatory defense and competition. This study delves into the insulin-like peptides (ILPs) present in sea anemones, particularly focusing on their role in potentially inducing hypoglycemic shock in prey. We identified five distinct ILPs in Exaiptasia diaphana, exhibiting varied sequences. Among these, ILP-Ap04 was successfully synthesized using solid phase peptide synthesis (SPPS) to evaluate its hypoglycemic activity. When tested in zebrafish, ILP-Ap04 significantly reduced blood glucose levels in a model of diabetes induced by streptozotocin (STZ) and glucose, concurrently affecting the normal locomotor behavior of zebrafish larvae. Furthermore, molecular docking studies revealed ILP-Ap04's unique interaction with the human insulin receptor, characterized by a detailed hydrogen-bonding network, which supports a unique mechanism for its hypoglycemic effects. Our findings suggest that sea anemones have evolved sophisticated strategies to activate insulin receptors in vertebrates, providing innovative insights into the design of novel drugs for the treatment of diabetes. [ABSTRACT FROM AUTHOR]

Dietary restriction (DR) is the most robust means to extend lifespan and delay age-related diseases across species. An underlying assumption in the aging field is that DR enhances both lifespan and physical activity through similar mechanisms, but this has not been rigorously tested in different genetic backgrounds. Furthermore, nutrient response genes responsible for lifespan extension or age-related decline in functionality remain underexplored in natural populations. To address this, we measured nutrient-dependent changes in lifespan and age-related decline in climbing ability in the Drosophila Genetic Reference Panel fly strains. On average, DR extended lifespan and delayed decline in climbing ability, but there was a lack of correlation between these traits across individual strains, suggesting that distinct genetic factors modulate these traits independently and that genotype determines response to diet. Only 50% of strains showed positive response to DR for both lifespan and climbing ability, 14% showed a negative response for one trait but not both, and 35% showed no change in one or both traits. Through GWAS, we uncovered a number of genes previously not known to be diet responsive nor to influence lifespan or climbing ability. We validated decima as a gene that alters lifespan and daedalus as one that influences age-related decline in climbing ability. We found that decima influences insulin-like peptide transcription in the GABA receptor neurons downstream of short neuropeptide F precursor (sNPF) signaling. Modulating these genes produced independent effects on lifespan and physical activity decline, which suggests that these age-related traits can be regulated through distinct mechanisms.

Abstract Background Insulin-like signaling (IS) in insects is a conserved pathway that regulates development, reproduction and longevity. Insulin-like peptides (ILPs) activate the IS pathway by binding to the insulin receptor (InR) and trigger the ERK and AKT cascades. A varying number of ILPs were identified in Aedes aegypti mosquito and other insects. Aedes albopictus is an invasive mosquito which transmits dengue and Zika viruses worldwide. Until now, the molecular and expression characteristics of IS pathway in Ae. albopictus have not been investigated. Methods The orthologues of ILP in Ae. albopictus genome assembly was analyzed by using sequence blast. Phylogenetic analysis and molecular characterization were performed to identify the functional domains of ILPs. Quantitative analysis was performed to determine the expression characteristics of ILPs, InR as well as ERK and AKT in mosquito development and different tissues of female adults after blood-feeding. In addition, the knockdown of InR was achieved by feeding larvae with Escherichia coli-producing dsRNA to investigate the impact of IS pathway on mosquito development. Results We identified seven putative ILP genes in Ae. albopictus genome assembly, based on nucleotide similarity to the ILPs of Ae. aegypti and other insects. Bioinformatics and molecular analyses suggested that the ILPs contain the structural motif which is conserved in the insulin superfamily. Expression levels of ILPs, InR as well as ERK and AKT varied in Ae. albopictus development stages and between male and female adults. Quantitative analyses revealed that expression of ILP6, the putative orthologue of the insulin growth factor peptides, was highest in the midgut of female adults after blood-feeding. Knockdown of Ae. albopictus InR induces a significant decrease in the phosphorylation levels of ERK and AKT proteins and results in developmental delays and smaller body sizes. Conclusions The IS pathway of Ae. albopictus mosquito contains ILP1-7, InR and ERK/AKT cascades, which exhibited different developmental and tissue expression characteristics. Feeding Ae. albopictus larvae with E. coli-producing InR dsRNA blocks the ERK and AKT cascades and interferes with the development of mosquito. Our data suggest that IS pathway plays an important role in the metabolism and developmental process and could represent a potential target for controlling mosquito-borne diseases. Graphical Abstract

Wing polyphenism is a common phenomenon that plays key roles in environmental adaptation of insects. Insulin/insulin‐like growth factor signaling (IIS) pathway is a highly conserved pathway in regulation of metabolism, development, and growth in metazoans. It has been reported that IIS is required for switching of wing morph in brown planthopper via regulating the development of the wing pad. However, it remains elusive whether and how IIS pathway regulates transgenerational wing dimorphism in aphid. In this study, we found that pairing and solitary treatments can induce pea aphids to produce high and low percentage winged offspring, respectively. The expression level of ILP5 (insulin‐like peptide 5) in maternal head was significantly higher upon solitary treatment in comparison with pairing, while silencing of ILP5 caused no obvious change in the winged offspring ratio. RNA interference‐mediated knockdown of FoxO (Forkhead transcription factor subgroup O) in stage 20 embryos significantly increased the winged offspring ratio. The results of pharmacological and quantitative polymerase chain reaction experiments showed that the embryonic insulin receptors may not be involved in wing polyphenism. Additionally, ILP4 and ILP11 exhibited higher expression levels in 1st wingless offspring than in winged offspring. We demonstrate that FoxO negatively regulates the wing morph development in embryos. ILPs may regulate aphid wing polyphenism in a developmental stage‐specific manner. However, the regulation may be not mediated by the canonical IIS pathway. The findings advance our understanding of IIS pathway in insect transgenerational wing polyphenism. [ABSTRACT FROM AUTHOR]

The neuropeptide pigment-dispersing factor (PDF) plays a pivotal role in the circadian clock of most Ecdysozoa and is additionally involved in the timing of seasonal responses of several photoperiodic species. The pea aphid, Acyrthosiphon pisum, is a paradigmatic photoperiodic species with an annual life cycle tightly coupled to the seasonal changes in day length. Nevertheless, PDF could not be identified in A. pisum so far. In the present study, we identified a PDF-coding gene that has undergone significant changes in the otherwise highly conserved insect C-terminal amino acid sequence. A newly generated aphid-specific PDF antibody stained four neurons in each hemisphere of the aphid brain that co-express the clock protein Period and have projections to the pars lateralis that are highly plastic and change their appearance in a daily and seasonal manner, resembling those of the fruit fly PDF neurons. Most intriguingly, the PDF terminals overlap with dendrites of the insulin-like peptide (ILP) positive neurosecretory cells in the pars intercerebralis and with putative terminals of Cryptochrome (CRY) positive clock neurons. Since ILP has been previously shown to be crucial for seasonal adaptations and CRY might serve as a circadian photoreceptor vital for measuring day length, our results suggest that PDF plays a critical role in aphid seasonal timing.

Background: Insulin-like signaling (IS) in insects is a conserved pathway that regulates development, reproduction and longevity. Insulin-like peptides (ILPs) activate the IS pathway by binding to the insulin receptor (InR) and trigger the ERK and AKT cascades. A varying number of ILPs were identified in Aedes aegypti mosquito and other insects. Aedes albopictus is an invasive mosquito which transmits dengue and Zika viruses worldwide. Until now, the molecular and expression characteristics of IS pathway in Ae. albopictus have not been investigated. Methods: The orthologues of ILP in Ae. albopictus genome assembly was analyzed by using sequence blast. Phylogenetic analysis and molecular characterization were performed to identify the functional domains of ILPs. Quantitative analysis was performed to determine the expression characteristics of ILPs, InR as well as ERK and AKT in mosquito development and different tissues of female adults after blood-feeding. In addition, the knockdown of InR was achieved by feeding larvae with Escherichia coli-producing dsRNA to investigate the impact of IS pathway on mosquito development. Results: We identified seven putative ILP genes in Ae. albopictus genome assembly, based on nucleotide similarity to the ILPs of Ae. aegypti and other insects. Bioinformatics and molecular analyses suggested that the ILPs contain the structural motif which is conserved in the insulin superfamily. Expression levels of ILPs, InR as well as ERK and AKT varied in Ae. albopictus development stages and between male and female adults. Quantitative analyses revealed that expression of ILP6, the putative orthologue of the insulin growth factor peptides, was highest in the midgut of female adults after blood-feeding. Knockdown of Ae. albopictus InR induces a significant decrease in the phosphorylation levels of ERK and AKT proteins and results in developmental delays and smaller body sizes. Conclusions: The IS pathway of Ae. albopictus mosquito contains ILP1-7, InR and ERK/AKT cascades, which exhibited different developmental and tissue expression characteristics. Feeding Ae. albopictus larvae with E. coli-producing InR dsRNA blocks the ERK and AKT cascades and interferes with the development of mosquito. Our data suggest that IS pathway plays an important role in the metabolism and developmental process and could represent a potential target for controlling mosquito-borne diseases. [ABSTRACT FROM AUTHOR]

Sea anemone venom, abundant in protein and peptide toxins, serves primarily for predatory defense and competition. This study delves into the insulin-like peptides (ILPs) present in sea anemones, particularly focusing on their role in potentially inducing hypoglycemic shock in prey. We identified five distinct ILPs in Exaiptasia diaphana, exhibiting varied sequences. Among these, ILP-Ap04 was successfully synthesized using solid phase peptide synthesis (SPPS) to evaluate its hypoglycemic activity. When tested in zebrafish, ILP-Ap04 significantly reduced blood glucose levels in a model of diabetes induced by streptozotocin (STZ) and glucose, concurrently affecting the normal locomotor behavior of zebrafish larvae. Furthermore, molecular docking studies revealed ILP-Ap04’s unique interaction with the human insulin receptor, characterized by a detailed hydrogen-bonding network, which supports a unique mechanism for its hypoglycemic effects. Our findings suggest that sea anemones have evolved sophisticated strategies to activate insulin receptors in vertebrates, providing innovative insights into the design of novel drugs for the treatment of diabetes.

The Australian red claw crayfish Cherax quadricarinatus, an emerging species within the freshwater aquaculture trade, is not only an ideal species for commercial production due to its high fecundity, fast growth, and physiological robustness but also notoriously invasive. Investigating the reproductive axis of this species has been of great interest to farmers, geneticists, and conservationists alike for many decades; however, aside from the characterisation of the key masculinising insulin-like androgenic gland hormone (IAG) produced by the male-specific androgenic gland (AG), little remains known about this system and the downstream signalling cascade involved. This investigation used RNA interference to silence IAG in adult intersex C. quadricarinatus (Cq-IAG), known to be functionally male but genotypically female, successfully inducing sexual redifferentiation in all individuals. To investigate the downstream effects of Cq-IAG knockdown, a comprehensive transcriptomic library was constructed, comprised of three tissues within the male reproductive axis. Several factors known to be involved in the IAG signal transduction pathway, including a receptor, binding factor, and additional insulin-like peptide, were found to not be differentially expressed in response to Cq-IAG silencing, suggesting that the phenotypic changes observed may have occurred through post-transcriptional modifications. Many downstream factors displayed differential expression on a transcriptomic level, most notably related to stress, cell repair, apoptosis, and cell proliferation. These results suggest that IAG is required for sperm maturation, with necrosis of arrested tissue occurring in its absence. These results and the construction of a transcriptomic library for this species will inform future research involving reproductive pathways as well as biotechnological developments in this commercially and ecologically significant species. [ABSTRACT FROM AUTHOR]

Aluminum is a well-known and widely distributed environmental neurotoxin. This study aimed to investigate the effect of miR-98-5p targeting insulin-like growth factor 2 (IGF2) on aluminum neurotoxicity. Thirty-two Sprague-Dawley rats were randomly divided into four groups and administered 0, 10, 20, and 40 μmol/kg maltol aluminum [Al(mal) 3 ], respectively. They were intraperitoneally injected every other day for three months. PC12 cells were divided into four dose groups: 0, 100, 200, and 400 μmol/L Al(mal) 3 , and four intervention groups: inhibitor NC, Al(mal) 3 + inhibitor NC, miR-98-5p inhibitor, and Al(mal) 3 + miR-98-5p inhibitor. The Morris water maze was used to test the learning and memory abilities of rats. Hematoxylin and eosin staining was used to observe the arrangement and quantity of neurons in the CA1 area of the rat hippocampus. Cell viability was detected using the Cell Counting Kit-8. Cell apoptosis was detected using flow cytometry and the 5-ethynyl-2'-deoxyuridine assay. Real-time polymerase chain reaction and Western blotting were used to detect the expression levels of miR-98-5p, IGF2 mRNA, IGF2/Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) pathway proteins, and apoptosis-related proteins caspase3 and cleaved caspase3. The dual-luciferase assay was used to determine the targeting relationship between miR-98-5p and IGF2 mRNA. As the dose of aluminum exposure increased, the escape latency of rats gradually prolonged, and the target quadrant residence time and the number of crossing platforms gradually decreased. The arrangement of neurons in the hippocampal CA1 area was significantly loose, and their number gradually decreased. The total and early apoptosis rates of PC12 cells gradually increased, and the cell proliferation rate slowed down. Both in vivo and in vitro experimental results showed that with the increase of aluminum exposure dose, the relative expression levels of miR-98-5p and caspase3 and cleaved caspase3 proteins gradually increased, while the relative expression levels of IGF2 mRNA and IGF2, p-JAK2 (Tyr1007/1008), and p-STAT3 (Tyr705) proteins gradually decreased. After inhibiting miR-98-5p in the aluminum exposure group, the cell apoptosis rate and expression of apoptosis-related proteins decreased, and the expression of IGF2 mRNA and IGF2/JAK2/STAT3 proteins increased. These results indicate that miR-98-5p plays a vital role in aluminum-induced neurotoxicity by targeting IGF2.

Background: Acromegaly has a high risk of abnormal glucose metabolism. The complexity of the glucose time series index (CGI) is calculated from refined composite multi-scale entropy analysis of the continuous glucose monitoring (CGM) data. CGI is a new indicator of glucose imbalance based on ambulatory glucose monitoring technology, which allows for earlier response to glucose metabolism imbalance and correlates with patient prognosis., Objective: To compare the differences in glucose metabolic profile and CGI between acromegaly with normal glucose tolerance (NGT) and healthy subjects., Methods: Eight newly diagnosed patients with acromegaly (GH group) and eight age- and gender-matched healthy subjects (Control group) were included in this study. All participants underwent oral glucose tolerance test (OGTT) and 72-h CGM. A refined composite multi-scale entropy analysis was performed on the CGM data to calculate the CGI and we compare the differences in glycemic profiles and CGI between the two groups., Results: After OGTT, compared with the control group, patients in the GH group had higher 2 h blood glucose (BG) (mmol/L) [GH vs control, 6.7 (6.1, 7.0) vs 5.2 (3.8, 6.3), P  = 0.012], 3 h BG [5.1 (3.8, 6.5) vs 4.0 (3.4, 4.2), P = 0.046], mean BG [6.3 (6.1, 6.5) vs 5.5 (5.1, 5.9), P = 0.002], 2 h insulin (mU/L) [112.9 (46.8, 175.5) vs 34.1 (17.1, 55.6), P = 0.009], and 3 h insulin [26.8 (17.1, 55.4) vs 10.4 (4.2, 17.8), P = 0.016]. CGI was lower in the GH group [2.77 (1.92, 3.15) vs 4.2 (3.3, 4.8), P = 0.008]. Spearman's correlation analysis showed insulin-like growth factor (IGF) (r = -0.897, P < 0.001) and mean glucose (r = -0.717, P = 0.003) were significantly negatively correlated with CGI. Multiple linear stepwise regression showed that IGF-1 (r = -0.652, P = 0.028) was independent factor associated with CGI in acromegaly., Conclusion: IGF-1 was significantly associated with CGI, and CGI may serve as a novel marker to evaluate glucose homeostasis in acromegaly with normal glucose tolerance., Competing Interests: Compliance with ethical standards. Conflict of interest: The authors declare no competing interests., (© 2024. The Author(s).)

Background: Pulmonary hypertension (PH) is associated with endothelial dysfunction. However, the cause of endothelial dysfunction and its impact on PH remain incompletely understood. We aimed to investigate whether the hypoxia-inducible FUNDC1 (FUN14 domain-containing 1)-dependent mitophagy pathway underlies PH pathogenesis and progression., Methods: We first analyzed FUNDC1 protein levels in lung samples from patients with PH and animal models. Using rodent PH models induced by HySu (hypoxia+SU5416) or chronic hypoxia, we further investigated PH pathogenesis and development in response to global and cell-type-specific Fundc1 loss/gain-of-function. We also investigated the spontaneous PH in mice with inducible loss of endothelial Fundc1 . In addition, histological, metabolic, and transcriptomic studies were performed to delineate molecular mechanisms. Finally, findings were validated in vivo by compound deficiency of HIF2α (hypoxia-inducible factor 2α; Epas1 ) and pharmacological intervention., Results: FUNDC1 protein levels were reduced in PH lung vessels from clinical subjects and animal models. Global Fundc1 deficiency exacerbated PH, while its overexpression was protective. The effect of FUNDC1 was mediated by endothelial cells rather than smooth muscle cells. Further, inducible loss of endothelial Fundc1 in postnatal mice was sufficient to cause PH spontaneously, whereas augmenting endothelial Fundc1 protected against PH before and after the onset of disease. Mechanistically, Fundc1 deficiency impaired basal mitophagy in endothelial cells, leading to the accumulation of dysfunctional mitochondria, metabolic reprogramming toward aerobic glycolysis, pseudohypoxia, and senescence, likely via a mtROS-HIF2α signaling pathway. Subsequently, Fundc1 -deficient endothelial cells increased IGFBP2 (insulin-like growth factor-binding protein 2) secretion that drove pulmonary arterial remodeling to instigate PH. Finally, proof-of-principle in vivo studies showed significant efficacy on PH amelioration by targeting endothelial mitophagy, pseudohypoxia, senescence, or IGFBP2., Conclusions: Collectively, we show that FUNDC1-mediated basal mitophagy is critical for endothelial homeostasis, and its disruption instigates PH pathogenesis. Given that similar changes in FUNDC1 and IGFBP2 were observed in PH patients, our findings are of significant clinical relevance and provide novel therapeutic strategies for PH., Competing Interests: None.

Investigating the genetic factors influencing human birth weight may lead to biological insights into fetal growth and long-term health. We report analyses of rare variants that impact birth weight when carried by either fetus or mother, using whole exome sequencing data in up to 234,675 participants. Rare protein-truncating and deleterious missense variants are collapsed to perform gene burden tests. We identify 9 genes; 5 with fetal-only effects on birth weight, 1 with maternal-only effects, 3 with both, and observe directionally concordant associations in an independent sample. Four of the genes were previously implicated by GWAS of birth weight. IGF1R and PAPPA2 (fetal and maternal-acting) have known roles in insulin-like growth factor bioavailability and signalling. PPARG, INHBE and ACVR1C (fetal-acting) are involved in adipose tissue regulation, and the latter two also show associations with favourable adiposity patterns in adults. We highlight the dual role of PPARG (fetal-acting) in adipocyte differentiation and placental angiogenesis. NOS3 (fetal and maternal-acting), NRK (fetal), and ADAMTS8 (maternal-acting) have been implicated in placental function and hypertension. To conclude, our analysis of rare coding variants identifies regulators of fetal adipose tissue and fetoplacental angiogenesis as determinants of birth weight, and further evidence for the role of insulin-like growth factors., Competing Interests: Competing interests: J.R.B.P. and E.J.G. are employees/shareholders of Insmed. J.R.B.P. also receives research funding from GSK and consultancy fees from WW International. Y.Z. is a UK University worker at GSK. S.O. has undertaken remunerated consultancy work for Pfizer, Third Rock Ventures, AstraZeneca, NorthSea Therapeutics and Courage Therapeutics. V.S., V.T., T.O., G.T., and K.S. are employees of deCODE genetics, a subsidiary of Amgen. The remaining authors declare no competing interests., (© 2025. The Author(s).)

Background and Objectives: Insulin-like growth factor-1 (IGF-1) plays a vital role in various cellular processes, including those involving stem cells. This study evaluated the effects of IGF-1 on cell survival, osteogenic differentiation, and mRNA expression in gingiva-derived mesenchymal stem cell spheroids. Materials and Methods: Using concave microwells, spheroids were generated in the presence of IGF-1 at concentrations of 0, 10, and 100 ng/mL. Cellular vitality was qualitatively assessed using microscopy, while a water-soluble tetrazolium salt-based assay kit quantified cellular viability. Osteogenic differentiation was evaluated via alkaline phosphatase activity and an anthraquinone dye test to measure calcium deposition. Additionally, quantitative polymerase chain reaction (qPCR) analysis was performed to determine the expression of RUNX2 and COL1A1. Results: By day 1, the stem cell spheroids had successfully formed, and their morphology remained stable over the following 7 days. The IGF-1 concentrations tested showed no significant differences in cell viability. Similarly, alkaline phosphatase activity on day 7 revealed no observable changes. However, on day 7, the incorporation of IGF-1 led to an increase in Alizarin Red staining, indicative of enhanced calcium deposition. Notably, an IGF-1 concentration of 100 ng/mL significantly upregulated the expression of COL1A1. Conclusions: These findings suggest that IGF-1 supports the maintenance of cell viability and promotes the expression of COL1A1 in gingiva-derived mesenchymal stem cell spheroids, highlighting its potential role in enhancing osteogenic differentiation. Future research should include long-term studies to evaluate the sustainability of IGF-1-induced effects on stem cell spheroids.

Background: Insulin-like growth factor-1 (IGF-1) promotes neurogenesis, cell survival, and glial function, making it a promising candidate therapy in Alzheimer's disease (AD)., Objective: Long arginine 3-IGF-1 (LR3-IGF-1) is a potent IGF-1 analogue. We sought to determine whether intranasal (IN) LR3 treatment would delay cognitive decline and pathology in 5XFAD mice., Methods: Wildtype and 5XFAD male mice were treated for 7 months (3-10 months of age), with IN LR3-IGF-1 or IN Vehicle (Veh) (n = 19-27 mice/group). Behavior, memory, and brain imaging were assessed at 8-9 months of age and tissues collected at 10 months. A comprehensive amyloid-β (Aβ) profile and other pathologic features were conducted and supportive in vitro stimulation studies in BV-2 microglial cells were also performed., Results: In male 5XFAD mice, IN LR3-IGF-1 treatment improved body composition, but did not significantly alter cognitive symptoms, as assessed by multiple assays. In cortex, LR3 treatment improved some facets of pathology, including a reduction in filamentous plaques, and increase in inert plaques, corresponding with a reduction in low molecular weight Aβ oligomers. In vitro , uptake of Aβ 1-42 peptide by BV2 cells was enhanced by LR3-IGF-1, which was also found to promote gene pathways implicated in actin remodeling and endocytosis., Conclusions: LR3 promotes favorable effects on Aβ plaque remodeling in cortex of male 5XFAD mice but fails to preserve aspects of behavior or memory. While these data do not support LR3 as a monotherapy per se , they do warrant further investigation into its potential for combinatorial formulations aimed at targeting the complexity of AD.

Insulin-like growth factor-binding proteins (IGFBPs) regulate insulin-like growth factor (IGF) signaling, but IGFBP-specific functions are not well characterized in fishes. A line of rainbow trout ( Oncorhynchus mykiss ) lacking a functional IGFBP-2b was produced using gene editing and subsequent breeding to an F2 generation. This loss-of-function model [IGFBP-2b knockout (2bKO)] was subjected to either continuous feeding or feed deprivation (3 wk) followed by refeeding (1 wk). During continuous feeding, the 2bKO line displayed faster specific growth rate for both body weight and fork length, higher feed intake, and reduced feed conversion ratio compared with a wild-type (WT) line. However, loss of IGFBP-2b did not affect the feed deprivation or refeeding response in terms of weight loss or weight gain, respectively. Several components of the IGF/IGFBP system were affected by loss of IGFBP-2b. Total serum IGF-1 in the 2bKO line was reduced to 0.5- to 0.8-fold of the WT line, although the concentration of free serum IGF-1 was not affected. Gene expression differences include reduced abundance of igfbp1a1 , igfbp1b2 , igfbp5b2 , and igfbp6b1 transcripts and elevated igf2 and igfbp6b2 transcripts in liver of the 2bKO line. Collectively, these findings suggest that although IGFBP-2b is a carrier of circulating IGF-1 in salmonids, the presence of IGFBP-2a and compensatory responses of other IGF/IGFBP system components support an anabolic response that improved growth performance in the loss-of-function model. NEW & NOTEWORTHY Knocking out IGFBP-2b in rainbow trout improved food intake, growth performance, and feed conversion ratio and reduced serum IGF-1 by 0.5- to 0.8-fold, without changes in the concentration of free serum IGF-1. Based on these findings, we propose that, in addition to IGFBP-2b, the 32-kDa IGFBP (putative IGFBP-2a) also serves as a major carrier of circulating IGF-1 in salmonids.

Exercise has acute, positive effects on mood and can lead to antidepressant effects over time when repeated regularly. The mechanisms underlying the antidepressant effects of exercise training are not well known, limiting the prescription of exercise training for depression. Serum Insulin-Like Growth Factor-1 (IGF-1) appears dysregulated in those with Major Depressive Disorder (MDD), suggesting MDD could inhibit or alter the IGF-1 response to exercise. In healthy individuals, exercise has been shown to acutely increase serum IGF-1, which may act positively on the dysregulated IGF-1 system in MDD. Therefore, the purpose of this study was to examine the sensitivity of serum IGF-1 levels to an acute maximal exercise bout in adults with MDD and healthy controls. Additionally, clinical and behavioral factors of MDD are likely to affect this system, such as depression severity, antidepressant usage and physical activity habits. Baseline data were used from a larger trial in Germany (SPeED Study) collected from individuals with mild to moderate MDD (n=113) and healthy controls (n=34) that were matched for age, sex, and education. Demographics, depression severity (Hamilton Depression Rating Scale-17), self-reported antidepressant usage, MVPA (International Physical Activity Questionnaire-Short Form), and blood draws before and after a maximal exercise test were collected. Multiple linear regressions were conducted to determine relationships between depression severity, antidepressant usage, and physical activity with peripheral IGF-1 levels following acute exercise. Covariates included demographic factors and IGF-1 pre-exercise (baseline levels). Acute IGF-1 changes occurred similarly in depression (mean ± SD; 11.3 ± 12.9) as well as healthy adults (11.3 ± 20.4: p>0.05). Neither depression severity, antidepressant use, nor regular physical activity were significant predictors of peripheral IGF-1 levels at baseline or following exercise. Individuals with MDD are likely to have favorable exercise-induced IGF-1 changes regardless of clinical and behavioral differences. Acute exercise increases peripheral IGF-1 briefly, and in response to repeated exercise bouts, the IGF-1 system could normalize over time. The normalization of the IGF-1 system might be a possible mechanism underlying mood increases that occur during exercise with exercise training research warranted., Competing Interests: Declaration of Competing Interest None., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Age and insulin-like growth factor-1 (IGF-1) have an inverse association with cognitive decline and dementia. IGF-1 is known to have important pleiotropic functions beginning in neurodevelopment and extending into adulthood such as neurogenesis. At the cellular level, IGF-1 has pleiotropic signaling mechanisms through the IGF-1 receptor on neurons and neuroglia to attenuate inflammation, promote myelination, maintain astrocytic functions for homeostatic balances, and neuronal synaptogenesis. In preclinical rodent models of aging and transgenic models of IGF-1, increased IGF-1 improves cognition in a variety of behavioral paradigms along with reducing IGF-1 via knockout models being able to induce cognitive impairment. At the clinical levels, most studies highlight that increased levels of IGF-1 are associated with better cognition. This review provides a comprehensive and up-to-date evaluation of the association between IGF-1 and cognition at the cellular signaling levels, preclinical, and clinical levels., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The Main Problem: Squamous cell carcinoma is the second most prevalent type of non-small cell lung cancer. Analyzing the molecular mechanisms underlying lung carcinoma requires useful tools, such as squamous lung cancer cell lines., Methods: A novel new lung squamous cell carcinoma cell line, OMUL-1, was developed from the primary lung cancer of a 74-year-old man. We assessed the characteristics and behavior of OMUL-1 cells were examined, including their growth kinetics, tumorigenicity in mice, histological properties, gene expression profiles using reverse transcription polymerase chain reaction (RT-PCR), and RNA sequencing and invasion assays., Results: OMUL-1-an adherent cell line-resulted in 100% tumor formation when subcutaneously injected into mice. Histological analysis of the subcutaneous tumor using hematoxylin and eosin staining revealed squamous cell carcinoma with characteristics similar to those of the primary tumor (p40 and p63 were positive, and TTF-1 was negative). An invasion assay demonstrated that OMUL-1 had a lower invasion ability compared to that of other developed cell lines. RT-PCR analysis and RNA sequencing indicated that OMUL-1 cells expressed FGFR1, FGFR2, FGFR3, FGFR4, EGFR, HER2, ErbB3, ErbB4, VEGFR3, IGF1R, c-MET, PDGFRa, and PDGFRb. Additionally, picropodophyllin (an IGF1R inhibitor) significantly inhibited the growth of OMUL-1 cells. Immunohistochemistry revealed that IGF1R and PD-L1 were expressed in both the primary and subcutaneous tumors., Conclusions: We developed a novel new squamous cell lung carcinoma cell line, OMUL-1, that expresses IGF1R and PD-L1., (© 2024 The Author(s). Thoracic Cancer published by John Wiley & Sons Australia, Ltd.)

The elongation of primary feathers in neonatal chicks is delayed by the late-feathering K gene located on the Z chromosome. We recently found that the K gene slows feather growth by reducing the number of functional prolactin (PRL) receptor (PRLR) dimers. In this study, we investigated the molecular mechanisms by which PRL promotes feather elongation. RT-qPCR and immunohistochemistry analyses revealed that PRLRs are predominantly localized in the pulp rather than in the epidermal layer of the feather follicle. Treatment of primary cultured feather pulp cells with PRL increased the expression of mRNAs for insulin-like growth factors (IGFs; IGF-1 and IGF-2) and type 2 deiodinase (DIO2). Furthermore, treatments with IGF-1 and triiodothyronine (T3) reciprocally enhanced the expression of mRNAs for DIO2 and IGFs. Additionally, BrdU staining in neonatal chicks showed that T3 promoted cell proliferation in both the epidermal layer and pulp cells, while this effect was suppressed by an IGF-1 receptor (IGF1R) inhibitor. These findings suggest a novel model in which PRL upregulates IGFs and DIO2 in feather pulp cells, creating a positive feedback loop between IGFs and T3, ultimately leading to the promotion of cell proliferation in both the epidermal layer and the pulp cells by IGFs. This is the first report proposing crosstalk between PRL, thyroid hormone (TH), and IGFs in feather follicles., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background and Aims: We aimed to characterise insulin-like growth factor-1 (IGF-1) signalling in patients with advanced chronic liver disease (ACLD)., Methods: Consecutive patients undergoing hepatic venous pressure gradient [HVPG] measurement were prospectively included. Clinical stages were defined as follows: probable ACLD (pACLD): liver stiffness ≥10 kPa and HVPG ≤5 mmHg, S0: mild PH (HVPG 6-9 mmHg), S1: clinically significant PH (CSPH), S2: CSPH with varices, S3: past variceal bleeding, S4: past/current non-bleeding hepatic decompensation and S5: further decompensation., Results: In total, 269 patients were included; 105 were compensated (pACLD: n = 18; S0: n = 30; S1: n = 20; S2: n = 37), and 164 were decompensated (S3: n = 11; S4: n = 89; S5: n = 64). Median levels of IGF-1 decreased with progressive cirrhosis (from pACLD: 88.5 ng/mL to S5: 51.0 ng/mL; p < 0.001). Patients with CSPH had significantly lower IGF-1 levels (63.5 ng/mL vs. 81.0 ng/mL; p = 0.001). IGF-1 showed an independent negative association with body mass index (BMI; aB: -1.56; p < 0.001), enhanced liver fibrosis (ELF) test (aB: -8.43; p < 0.001), MELD (aB: -1.13; p = 0.042) and age (per 10 years; aB: -6.87; p < 0.001). IGF-1 exhibited an excellent AUROC (0.856) for the prediction of liver-related death at 6 months of follow-up. Lower IGF-1 (per 10 ng/mL) was linked to higher risk of (further) decompensation (0.90; 95% CI: 0.83-0.98; p = 0.016), acute-on-chronic liver failure (ACLF; asHR: 0.80; 95% CI: 0.68-0.93; p = 0.004) and liver-related death (asHR: 0.76; 95% CI: 0.63-0.91; p = 0.004)., Conclusion: Decreased levels of IGF-1 reflect impaired hepatic function and fibrogenesis in patients with cirrhosis, which seems particularly relevant in obesity since low IGF-1 was independently linked to high BMI. Lower IGF-1 in cirrhosis predicts decompensation, ACLF and liver-related death., (© 2024 The Author(s). Alimentary Pharmacology & Therapeutics published by John Wiley & Sons Ltd.)

Muscle atrophy secondary to disuse, aging, or illness increases the risk of injury, prolonged recovery, and permanent disability. The recovery process involves macrophages and their secretions, such as insulin-like growth factor 1 (IGF-1), which direct muscle to regenerate and grow. Retinoic acid receptor (RAR) activation in macrophages increases IGF-1 expression and can be achieved with all-trans retinoic acid (ATRA). However, poor bioavailability limits its clinical application. Thus, we encapsulated ATRA into poly(lactide-co-glycolide) microparticles (ATRA-PLG) to maintain bioactivity and achieve extended release. ATRA-PLG induces IGF-1 release by RAW 264.7 macrophages, and conditioned media from these cells enhances C2C12 myotube formation through IGF-1. Additionally, ATRA released from ATRA-PLG enhances myotube formation in the absence of macrophages. Toward clinical translation, we envision that ATRA-PLG will be injected in the vicinity of debilitated muscle where it can be taken up by macrophages and induce IGF-1 release over a predetermined therapeutic window. Along these lines, we demonstrate that ATRA-PLG microparticles are readily taken up by bone marrow-derived macrophages and reside within the cytosol for at least 12 days with no toxicity. Interestingly, ATRA-PLG induced IGF-1 secretion by thioglycolate-elicited macrophages, but not bone marrow derived macrophages. We found that the RAR isoforms present in lysate differed between the macrophages studied, which could explain the different IGF-1 responses to ATRA. Given that ATRA-PLG enhances myotube formation directly (through ATRA) and indirectly (through macrophage IGF-1) this study supports the further testing of this promising pharmaceutical using rodent models of muscle regeneration and growth., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Published by Elsevier B.V.)

Background: Immigrants from the Middle East (ME) have a higher prevalence of type 2 diabetes (T2D) compared to the native-born Swedish population. In individuals free from T2D, ME immigrants are more insulin resistant and have lower levels of adjusted insulin secretion (Disposition index, DIo) compared to Swedish-born individuals. The ethnic differences are not fully explained by traditional risk factors. This has raised the question as to whether hormonal factors other than insulin are involved, contributing to higher T2D risk in ME immigrants., Aims: In ME immigrants at high risk of developing T2D, we aimed to study the effect of a randomized culturally adapted lifestyle intervention on the levels of Vitamin D (25(OH)D), insulin-like growth factor 1 (IGF-1), Pro-neurotensin (Pro-NT) and Adiponectin. Furthermore, we aimed to study if the effect of the intervention was associated to these hormones, or if a direct effect of the intervention remained after accounting for these., Methods: In this culturally adapted randomized controlled trial of four months duration, eligible ME immigrants at high risk of developing T2D identified in the MEDIM cohort were invited to participate. The intervention group (N= 35) received a culturally adapted lifestyle intervention program consisting of seven group sessions and cooking classes. The control group (N= 32) were given treatment as usual with oral and written information to improve their lifestyle habits. Using mixed models' linear regression analysis, the changes in the levels of 25(OH)D, IGF-1, Adiponectin and Pro-NT were assessed by comparing the groups and we further studied the effects of the changes on insulin action and secretion., Results: The adjusted levels of 25(OH)D significantly increased in the intervention group compared to the control group (β for the effect of the intervention on 25(OH)D: 0.061, 95 % CI 0.009-0.113, P = 0.023). The increase in insulin sensitivity index (ISI) observed in the intervention compared to the control group was altered after adjusting for 25(OH)D: 0.129, 95 % CI -0.016-0.274, P = 0.078). IGF-1, Adiponectin and Pro-NT did not significantly influence the change over time concerning insulin secretion., Conclusion: Lifestyle intervention increases the adjusted levels of 25(OH)D. Moreover, the effect of the lifestyle intervention on insulin action and secretion was altered when adjusting for 25(OH)D., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Adiposity is positively associated with risk of some cancer sites and other health conditions in men; however, it is unclear if endogenous hormones play a role in these associations. We examined how body composition, measured from magnetic resonance imaging (MRI) and common measures of adiposity (e.g., body mass index (BMI)), are related to hormone concentrations in men from the UK Biobank study., Methods: Up to 16,237 men with available body composition data (including visceral, subcutaneous, and liver fat, muscle fat infiltration (MFI), lean tissue, and common adiposity measures) and serum hormone measurements (insulin-like growth factor-I (IGF-I), total testosterone, sex hormone-binding globulin (SHBG), and calculated free testosterone) were included. Multivariable-adjusted linear regression models were used to determine the geometric mean hormone and SHBG concentrations across categories of each exposure., Results: Common measurements of adiposity were highly correlated with MRI measures of central and total adiposity (r = 0.76-0.91), although correlations with ectopic fat (liver fat and MFI) were lower (r = 0.43-0.54). Most adiposity measurements showed an inverse U- or J-shaped association with circulating IGF-I and free testosterone; however, MFI was linearly inversely associated, and lean tissue volume was positively associated with both IGF-I and free testosterone concentrations. All body composition measures were inversely associated with total testosterone and SHBG concentrations (relative geometric mean difference between Q5 vs. Q1: 20-30%)., Conclusion: Our results show that common adiposity and most MRI measures of adiposity relate similarly to serum hormone concentrations; however, associations with ectopic fat (particularly MFI) and lean tissue were different., Competing Interests: Competing interests: The authors declare no competing interests. Ethical approval: The UK Biobank has received ethics approval from the North West Multi-centre Research Ethics Committee (2021 approval reference 16/NW/0274). All participants provided informed consent to participate at recruitment. Our research required no additional ethical clearance., (© 2024. The Author(s).)

Background: Insulin-like growth factor (IGF)-1 plays a role in aging and cancer biology, with fasting known to reduce serum IGF-1 levels in human adults. However, the impact of ad libitum ketogenic diets (KDs) on IGF-1 levels remains unclear., Methods: Adhering to PRISMA guidelines, we conducted a meta-analysis of human trials by systematically searching Ovid, PubMed, Scopus, and CENTRAL Libraries until June 2023. Eligible studies prescribed KDs to adults of any health status, confirmed ketosis, and measured serum IGF-1. Protocols involving prescribed fasting or energy restriction were excluded. Mean differences (MD) and 95 % confidence intervals (CIs) were calculated longitudinally between pre- and post-intervention measurements for the KD groups., Results: Among twelve publications meeting the inclusion criteria, 522 individuals participated, with 236 completing KDs. The intervention duration ranged from 1 to 20 weeks. Pooled results from ten trials showed a significant reduction in serum IGF-1 levels post-intervention (MD: -24.9 ng/mL [95 % CI -31.7 to -18.1]; p<0.0001) with low heterogeneity across studies (I 2 =27 %, p=0.19). KDs were also associated with significantly decreased fasting insulin (MD: -2.57 mU/L [95 % CI -4.41 to -0.74], p=0.006) and glucose (MD: -7.30 mg/dL [95 % CI -11.62 to -2.98], p=0.0009), although heterogeneity was significant. Subgroup analyses on study design, gender, dietary duration, and oncological status revealed no significant differences., Conclusion: Ad libitum KDs (>55 % fat) effectively induce ketosis and can lower serum IGF-1 by 20 %, fasting glucose by 6 % and insulin by 29 %. This clinically notable reduction in IGF-1 can be attained without the need for a prescribed fasting or severe calorie restriction regimen. Further investigation is warranted to explore the impact of KDs on ageing biomarkers and cancer management., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

The regeneration of osteochondral defects is challenging due to the complex structure of the osteochondral unit. This study aimed to develop a biomimetic scaffold by loading growth hormone (GH) and insulin-like growth factor-1 (IGF-1) into poly (lactic-co-glycolic acid) (PLGA) nanoparticles and incorporating them into polycaprolactone (PCL) scaffolds to promote synchronized osteochondral regeneration. The nanoparticles were successfully immobilized onto PCL scaffolds pre-modified with polydopamine (PDA) to enhance cell adhesion and proliferation. The scaffolds exhibited a sustained release of GH and IGF-1 over 30 days. In vitro studies using rabbit adipose-derived stem cells (ADSCs) showed that the GH/IGF-1 nanoparticle-loaded scaffolds (PCL/PDA/M-PLGA) significantly promoted cell proliferation, chondrogenic differentiation, and osteogenic differentiation compared to control PCL/PDA scaffolds. In vivo experiments using a rabbit osteochondral defect model revealed that the PCL/PDA/M-PLGA scaffolds facilitated superior osteochondral regeneration, evidenced by increased subchondral bone formation and cartilage matrix deposition. Overall, this study demonstrates the potential of GH/IGF-1 nanoparticle-loaded PCL scaffolds for synchronized osteochondral regeneration and provides a promising strategy for treating osteochondral defects., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Objective: To validate a serum biomarker developed in the USA for preterm birth (PTB) risk stratification in Viet Nam., Methods: Women with singleton pregnancies ( n  = 5000) were recruited between 19 +0 -23 +6 weeks' gestation at Tu Du Hospital, Ho Chi Minh City. Maternal serum was collected from 19 +0 -22 +6 weeks' gestation and participants followed to neonatal discharge. Relative insulin-like growth factor binding protein 4 (IGFBP4) and sex hormone binding globulin (SHBG) abundances were measured by mass spectrometry and their ratio compared between PTB cases and term controls. Discrimination (area under the receiver operating characteristic curve, AUC) and calibration for PTB <37 and <34 weeks' gestation were tested, with model tuning using clinical factors. Measured outcomes included all PTBs (any birth ≤37 weeks' gestation) and spontaneous PTBs (birth ≤37 weeks' gestation with clinical signs of initiation of parturition)., Results: Complete data were available for 4984 (99.7%) individuals. The cohort PTB rate was 6.7% ( n  = 335). We observed an inverse association between the IGFBP4/SHBG ratio and gestational age at birth ( p  = 0.017; AUC 0.60 [95% CI, 0.53-0.68]). Including previous PTB (for multiparous women) or prior miscarriage (for primiparous women) improved performance (AUC 0.65 and 0.70, respectively, for PTB <37 and <34 weeks' gestation). Optimal performance (AUC 0.74) was seen within 19-20 weeks' gestation, for BMI >21 kg/m2 and age 20-35 years., Conclusion: We have validated a novel serum biomarker for PTB risk stratification in a very different setting to the original study. Further research is required to determine appropriate ratio thresholds based on the prevalence of risk factors and the availability of resources and preventative therapies.

Background: Malnutrition is common among children with congenital heart disease (CHD). We compared the anthropometric indices, serum insulin-like growth factor (IGF), and IGF acid-labile subunit (IGFALS) of children with cyanotic and acyanotic CHD before corrective surgery., Methods: This 82-patient case-control study included 1- to 24-month-old CHD patients referred for corrective surgery. (41 with tetralogy of Fallot [TOF] and 41 with ventricular septal defect [VSD] or atrial septal defect [ASD]). Anthropometric indices represented as Z-scores were used to determine nutritional status. Serum IGF-1 and IGFALS levels were measured., Results: The median [quartile] age of the acyanotic group was 8 [7,11] months which was lower than the cyanotic group (11 [8,14.5] months). The prevalence of underweight (weight for age Z [WAZ] < -2), wasting (weight for length Z [WLZ] < -2), and thinness (body mass index Z [BMIZ] < -2) was significantly higher in children with acyanotic than cyanotic children with. WAZ, WLZ, and BMIZ were significantly lower in acyanotic children than cyanotic children with CHD (-2.5 ± 1.2 vs -1.0 ± 1.2, p < 0.001 for WAZ, -2.5 ± 1.5 vs -0.8 ± 1.4, p < 0.001 for WLZ, and -2.5 ± 1.5 vs -0.8 ± 1.4, p < 0.001 for BMIZ), but length for age Z was not different between the two groups (-1.2 ± 1.0 vs -0.8 ± 1.1, p = 0.31). A comparison of preoperative serum albumin, IGF-1, and IGFALS showed no differences., Conclusions: In CHD children without corrective surgery, moderate to severe underweight and wasting were more common in acyanotic CHD (VSD and ASD) than in cyanotic CHD (TOF), but the higher prevalence of malnutrition was not associated with lower IGF-1 and IGFALS levels., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024 European Society for Clinical Nutrition and Metabolism. Published by Elsevier Ltd. All rights reserved.)

Background: Preterm birth disrupts fetal kidney development, potentially leading to postnatal acute kidney injury. Preterm infants are deficient in insulin-like growth factor 1 (IGF-1), a growth factor that stimulates organ development. By utilizing a preterm pig model, this study investigated whether IGF-1 supplementation enhances preterm kidney maturation., Methods: Cesarean-delivered preterm pigs were treated systemically IGF-1 or vehicle control for 5, 9 or 19 days after birth. Blood, urine, and kidney tissue were collected for biochemical, histological and gene expression analyses. Age-matched term-born pigs were sacrificed at similar postnatal ages and served as the reference group., Results: Compared with term pigs, preterm pigs exhibited impaired kidney maturation, as indicated by analyses of renal morphology, histopathology, and inflammatory and injury markers. Supplementation with IGF-1 reduced signs of kidney immaturity, particularly in the first week of life, as indicated by improved morphology, upregulated expression of key developmental genes, reduced severity and incidence of microscopic lesions, and decreased levels of inflammatory and injury markers. No association was seen between the symptoms of necrotizing enterocolitis and kidney defects., Conclusion: Preterm birth in pigs impairs kidney maturation and exogenous IGF-1 treatment partially reverses this impairment. Early IGF-1 supplementation could support the development of preterm kidneys., Impact: Preterm birth may disrupt kidney development in newborns, potentially leading to morphological changes, injury, and inflammation. Preterm pigs have previously been used as models for preterm infants, but not for kidney development. IGF-1 supplementation promotes kidney maturation and alleviates renal impairments in the first week of life in preterm pigs. IGF-1 may hold potential as a supportive therapy for preterm infants sensitive to acute kidney injury., Competing Interests: Competing interests: Author P.T.S., T.T., D.N.N., and T.M. are currently involved in a patent application directed to use of rhIGF-1 for preterm infants. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2024. The Author(s).)

Mesenchymal stem cells (ADMSCs) have been applied to the treatment of skin injuries and the co-administration of cytokines can enhance the effects. In the current study, the promoting effects of insulin-like growth factor 1 (IGF-1) on the skin wound healing effects of adipose-derived MSCs (ADMSCs) were assessed and the associated mechanism was explored by focusing on miR-21-5p mediated pathways. ADMSCs were isolated from epididymis rats, and skin wounded rats were employed as the in vivo model for evaluating the effect of ADMCs on skin healing and secretion of cytokines. Then a microarray assay was employed to select potential miR target of IGF-1 on ADMSCs. The level of the selected miR was modulated in ADMSCs, and the effects on skin injuries were also assessed. Administration of ADMSCs promoted skin wound healing and induced the production of bFGF, IL-1β, PDGF, SDF-1, IGF-1, and TNF-α. The co-administration of IGF-1 and ADMSCs strengthened the effect of ADMSCs on skin wound by suppressing activity of matrix metalloproteinase-1 (MMP-1). At molecular level, the treatment of IGF-1 up-regulated miR-21-5p level in ADMSCs, which then suppressed the expression of KLF6 in injured skin tissues and promoted wound healing. The inhibition of miR-21-5p counteracted the promoting effects of IGF-1 on the skin healing effects of ADMSCs. Findings outlined in the current study indicated that IGF-1 could promote the wound healing effects of ADMSCs by up-regulating miR-21-5p level., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Ltd.)

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., (© 2024 John Wiley & Sons Ltd.)

Objectives: The insulin receptor (IR) and insulin like growth factor-1 receptor (IGF-1R) are heterodimers consisting of two extracellular α-subunits and two transmembrane β -subunits. Insulin αβ and insulin like growth factor-1 αβ hemi-receptors can heterodimerize to form hybrids composed of one IR αβ and one IGF-1R αβ. The function of hybrids in the endothelium is unclear. We sought insight by developing a small molecule capable of reducing hybrid formation in endothelial cells., Methods: We performed a high-throughput small molecule screening, based on a homology model of the apo hybrid structure. Endothelial cells were studied using western blotting and qPCR to determine the effects of small molecules that reduced hybrid formation., Results: Our studies unveil a first-in-class quinoline-containing heterocyclic small molecule that reduces hybrids by >50% in human umbilical vein endothelial cells (HUVECs) with no effects on IR or IGF-1R. This small molecule reduced expression of the negative regulatory p85α subunit of phosphatidylinositol 3-kinase, increased basal phosphorylation of the downstream target Akt and enhanced insulin/insulin-like growth factor-1 and shear stress-induced serine phosphorylation of Akt. In primary saphenous vein endothelial cells (SVEC) from patients with type 2 diabetes mellitus undergoing coronary artery bypass (CABG) surgery, hybrid receptor expression was greater than in patients without type 2 diabetes mellitus. The small molecule significantly reduced hybrid expression in SVEC from patients with type 2 diabetes mellitus., Conclusions: We identified a small molecule that decreases the formation of IR: IGF-1R hybrid receptors in human endothelial cells, without significant impact on the overall expression of IR or IGF-1R. In HUVECs, reduction of IR: IGF-1R hybrid receptors leads to an increase in insulin-induced serine phosphorylation of the critical downstream signalling kinase, Akt. The underpinning mechanism appears, at least in part to involve the attenuation of the inhibitory effect of IR: IGF-1R hybrid receptors on PI3-kinase signalling., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Abnormal stromal-epithelial cell communication is a pathogenic mechanism in endometriosis, and metformin can modulate it. Insulin-like growth factor binding protein-1 (IGFBP1) plays a role in endometriosis, but the exact mechanism is unknown. IGFBP1 is reportedly a downstream target of metformin in some diseases. We aimed to investigate the role of IGFBP1 in endometriosis development, whether it is associated with abnormal communication, and whether metformin affects IGFBP1 expression., Methods: Patients who underwent surgical treatment for endometriosis or other diseases were enrolled. Ten patients with ovarian-type endometriosis and eight patients each who underwent surgical treatment for other lesions with or without endometriosis were selected, and their tissues taken for cell proliferation, western blotting, polymerase chain reaction, and knockdown experiments., Results: Ectopic and eutopic stromal cells (EcSCs and EuSCs) lost their ability to inhibit epithelial cell proliferation, and IGFBP1 expression was downregulated in both groups of stromal cells compared to that in normal stromal cells (NSCs; 1.09 vs. 0.25, p  = .0002 1.09 vs. 0.57, p  = .0029). In an EcSC IGFBP1 overexpression model, the ability of EcSCs to inhibit epithelial cell proliferation was enhanced (EdU positivity decreased from 38% to 25%, p  = .0001). Furthermore, adenosine 5'-monophosphate-activated protein kinase (AMPK) phosphorylation was downregulated in EcSCs and EuSCs compared to that in NSCs (0.99 vs. 0.42, p  = .0006/0.99 vs. 0.57, p  = 0.0032). Treatment of EcSCs with metformin increased AMPK phosphorylation (0.47 vs. 1.04, p  = .0107) while upregulating IGFBP1 expression (0.69 vs. 1.01, p  = .0164), whereas pre-treatment with an AMPK phosphorylation inhibitor abrogated metformin-induced IGFBP1 upregulation., Conclusions: IGFBP1 mediates aberrant stromal-epithelial communication in endometriosis. Metformin can upregulate IGFBP1 expression in EcSCs by activating AMPK, and upregulated IGFBP1 enhances the inhibition of epithelial cell proliferation. IGFBP1 is expected to be a therapeutic target for endometriosis.

Introduction: We evaluate the predictive and prognostic value of insulin-like growth factor-I (IGF-1), IGF binding protein-2 (IGFBP-2) and -3 (IGFBP-3) in patients treated with radical nephroureterectomy (RNU) for upper tract urothelial carcinoma (UTUC)., Methods: This is a retrospective analysis of a multi-institutional database comprising 753 patients who underwent RNU for UTUC and had a preoperative plasma available. Logistic and Cox regression analyses were performed. The discriminative ability and clinical utility of the models was calculated using the lasso regression test, area under receiver operating characteristics curves, C-index, and decision curve analysis (DCA)., Results: Lower preoperative plasma levels of IGFBP-2 and -3 independently correlated with increased risks of lymph node metastasis, pT3/4 disease, nonorgan confined disease, and worse recurrence-free survival (RFS), cancer-specific survival (CSS), and overall survival (OS) (all P ≤ .004). The addition of both IGFBP-2 and -3 to a postoperative multivariable model, that included standard clinicopathologic characteristics, improved the model's concordance index by 10%, 9%, and 8% for RFS, CSS, and OS, respectively. On DCA, addition of both IGFBP-2 and -3 to base models improved their performance for RFS, CSS, and OS by a statistically and clinically significant margin. Plasma IGF-1 was not associated with any of outcomes., Conclusions: We confirmed that a lower plasma levels of IGFBP-2 and -3 both are independent and clinically significant predictors of adverse pathological features and survival outcomes in UTUC patients treated with RNU. These findings might help guide the clinical decision-making regarding perioperative systemic therapy and follow-up scheduling., Competing Interests: Disclosure The authors have stated that they have no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Nutrient sensing and metabolic homeostasis play an important role in the proper growth and development of an organism, and also in the energy intensive process of reproduction. Signals in response to nutritional and metabolic status is received and integrated by the brain to ensure homeostasis. In Drosophila, the fat body is one of the key organs involved in energy and nutrient sensing, storage and utilization. It also relays the nutritional status of the animal to the brain, activating specific circuits which modulate the synthesis and release of insulin-like peptides to regulate metabolism. Here, we review the molecular and cellular mechanisms involved in nutrient sensing with an emphasis on the neural pathways that modulate this process and discuss some of the open questions that need to be addressed. [ABSTRACT FROM AUTHOR]

Nutrient sensing and metabolic homeostasis play an important role in the proper growth and development of an organism, and also in the energy intensive process of reproduction. Signals in response to nutritional and metabolic status is received and integrated by the brain to ensure homeostasis. In Drosophila, the fat body is one of the key organs involved in energy and nutrient sensing, storage and utilization. It also relays the nutritional status of the animal to the brain, activating specific circuits which modulate the synthesis and release of insulin-like peptides to regulate metabolism. Here, we review the molecular and cellular mechanisms involved in nutrient sensing with an emphasis on the neural pathways that modulate this process and discuss some of the open questions that need to be addressed.

Insulin‑like growth factor 2 mRNA binding protein 2 (IGF2BP2) is an RNA binding protein that functions as an N 6 ‑methyladenosine reader. It regulates various biological processes in human cancers by affecting the stability and expression of target RNA transcripts, including coding RNAs and non‑coding RNAs (ncRNAs). Numerous studies have shown that IGF2BP2 expression is aberrantly increased in various types of cancer and plays multifaceted roles in the development and progression of human cancers. In the present review, the clinical importance of IGF2BP2 is summarized and its involvement in the regulation of biological processes, including proliferation, metastasis, chemoresistance, metabolism, tumor immunity, stemness and cell death, in human cancers is discussed. The chemical compounds that have been developed as IGF2BP2 inhibitors are also detailed. As ncRNAs are now important potential therapeutic agents for cancer treatment, the microRNAs that have been reported to directly target and inhibit IGF2BP2 expression in cancers are also described. In summary, by reviewing the latest literature, the present study aimed to highlight the clinical importance and physiological functions of IGF2BP2 in human cancer, with a focus on the great potential of IGF2BP2 as a target for inhibitor development. The present review may inspire new ideas for future studies on IGF2BP2, which may serve as a specific therapeutic target in cancer.

Alzheimer's disease (AD) is the leading cause of dementia among the elderly population, posing a significant public health challenge due to limited therapeutic options that merely delay cognitive decline. AD is associated with impaired energy metabolism and reduced neurotrophic signaling. The insulin-like growth factor (IGF) signaling pathway, crucial for central nervous system (CNS) development, metabolism, repair, cognition, and emotion regulation, includes IGF-1, IGF-2, IGF-1R, IGF-2R, insulin receptor (IR), and six insulin-like growth factor binding proteins (IGFBPs). Research has identified abnormalities in IGF signaling in individuals with AD and AD models. Dysregulated expression of IGFs, receptors, IGFBPs, and disruptions in downstream phosphoinositide 3-kinase-protein kinase B (PI3K/AKT) and mitogen-activated protein kinase (MAPK) pathways collectively increase AD susceptibility. Studies suggest modulating the IGF pathway may ameliorate AD pathology and cognitive decline. This review explores the CNS pathophysiology of IGF signaling in AD progression and assesses the potential of targeting the IGF system as a novel therapeutic strategy. Further research is essential to elucidate how aberrant IGF signaling contributes to AD development, understand underlying molecular mechanisms, and evaluate the safety and efficacy of IGF-based treatments., Competing Interests: Declarations. Ethics Approval: Not applicable. Consent to Participate: Not applicable. Consent for Publication: Not applicable. Competing Interests: The authors declare no competing interests., (© 2024. The Author(s).)

Background: Previous researches on the effect of low-fat diet (LF) on insulin-like growth factor-1 (IGF-1), and its binding proteins (IGFBPs) did not reach a consensus result, and there is no study summarizing these findings. Thus, this systematic review and meta-analysis of randomized control trials (RCTs) was performed to pool available evidence and answer the question whether dietary fat can affect IGF-1 and IGFBPs or not., Methods: PubMed, Scopus, ISI Web of Science, Google, Google scholar, ProQuest, and the Cochrane Library were searched without language restrictions until July 2, 2024 to retrieve related studies. Weighted mean difference and the corresponding variance were considered as the effect size. Standard tools were applied to assess the quality of the studies and evidence., Results: Pooling data of the eligible studies showed no significant effect of LF diet on IGF-1 (six studies; participants = 1029.; pooled mean = 1.63 ng/ml, 95% CI= [-1.34, 4.59], P = 0.28, I 2  = 0.00%), and IGFBP-3 (five studies; participants = 969; pooled mean = 65.24 ng/ml, 95% CI= [-169.53, 300.00], P = 0.59, I 2  = 0.0%). The results of subgroup analysis for IGF-1 and IGFBP-3 also demonstrated no significant findings. For IGFBP-1, available evidence is insufficient since only two studies have been performed yet and their results are contradictory., Conclusions: This study indicated no significant effect of LF diet on IGF-1, and IGFBP-3 concentrations. Low certainty of evidence indicates that available evidence cannot support to draw a firm conclusion and future researches may change the estimates., Competing Interests: Declarations. Ethical statement: All data and analyses in this research were based on previous published studies, thus ethical approval and patient consent are not applicable for it. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Background: The insulin-like growth factor (IGF) system plays a vital role in regulating gonadotropin-releasing hormone (GnRH), whether the IGF2 can act on the GnRH neurons during the pubertal period is unclear., Methods: Central precocious puberty (CPP) rats were induced by danazol, and when the rats met the first diestrus, they were euthanized and tissues were collected. GT1-7 cells were cultured and treated with 0, 1, 10 ng/mL IGF2 for 4 hours and the changes in GnRH were measured. Mice were injected intracerebroventricularly with IGF2 (15 ng/g, 5 μL) or with the same dose of phosphate buffered saline (PBS), after eight hours, they were euthanized and tissues collected., Results: CPP rats had increased expression of IGF2 and GnRH mRNA and their respective proteins in the preoptic area (POA) of the hypothalamus. Treatment of GT1-7 cells with 10 ng/mL of IGF2 increased GnRH mRNA and protein expression, and GnRH concentration in the culture medium. Injection of IGF2 protein into the lateral ventricle of mice increased the expression of GnRH mRNA and protein in the POA., Conclusions: IGF2 may upregulate the synthesis of GnRH during the pubertal period, and may also take part in the pathology of CPP., (© 2024 The Author(s). Published by IMR Press.)

Insulin-like growth factor-binding protein-1 (IGFBP-1) contributes to the regulation of IGFs for metabolism and growth and has IGF-independent actions. IGFBP-1 in the circulation is derived from the liver, where it is inhibited by insulin and stimulated by multiple factors, including proinflammatory cytokines. IGFBP-1 levels are influenced by sex and age, which also determine cardiometabolic risk and patterns of disease presentation. While lower circulating IGFBP-1 concentrations are associated with an unfavorable cardiometabolic risk profile, higher IGFBP-1 predicts worse cardiovascular disease outcomes. This review explores these associations and the possible roles of IGFBP-1 in the pathophysiology of atherosclerosis. We recommend the evaluation of dynamic approaches, such as simultaneous measurements of fasting IGFBP-1 and proinsulin level in response to an oral glucose challenge, as well as multi-marker approaches incorporating markers of inflammation.

Background: Serum insulin-like growth factor 1 (IGF-1) is an important biochemical tool to diagnose and monitor growth hormone (GH)-related disorders. However, ethnicity-specific Indian data, following consensus criteria for the establishment of normative data, are not available. Our objective was to generate chronological age (CA)-, bone age (BA)- and Tanner stage-specific normative data for IGF-1 in healthy Indian children and adolescents., Methods: A cross-sectional epidemiological study was conducted in schools and the community, which enrolled apparently healthy children and adolescents with robust exclusion criteria. The outcome measure was serum IGF-1 assessed using an electro-chemiluminescence immunoassay (ECLIA). The 2.5th, 5th, 10th, 25th, 50th (median), 75th, 90th, 95th, and 97.5th centiles for IGF-1 were estimated using generalized additive models., Results: We recruited 2226 apparently healthy participants and following exclusion, 1948 (1006 boys, 942 girls) were included in the final analysis. Girls had median IGF-1 peak at CA of 13 years (321.7 ng/mL), BA of 14 years (350.2 ng/mL) and Tanner stage IV (345 ng/mL), while boys had median IGF-1 peak at CA of 15 years (318.9 ng/mL) BA of 15 years (340.6 ng/mL) and Tanner stage III (304.8 ng/mL). Girls had earlier rise, earlier peak, and higher IGF-1 values. The reference interval (2.5th to 97.5th percentile) was broader during peripubertal ages, indicating a higher physiological variability., Conclusion: This study provides ethnicity-specific normative data on serum IGF-1 and will improve the diagnostic utility of IGF-1 in the evaluation and management of growth disorders in Indian children and adolescents., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com. See the journal About page for additional terms.)

T cell exclusion is crucial in enabling tumor immune evasion and immunotherapy resistance. However, the key genes driving this process remain unclear. We uncovered a notable increase of insulin-like growth factor 2 (IGF2) in immune-excluded tumors, predominantly secreted by cancer-associated fibroblasts (CAFs). Using mice with systemic or fibroblast-specific deletion of IGF2, we demonstrated that IGF2 deficiency enhanced the infiltration and cytotoxic activity of CD8+ T cells, leading to a reduction in tumor burden. Integration of spatial and single-cell transcriptomics revealed that IGF2 promoted interaction between CAFs and T cells via CXCL12 and programmed death ligand 1 (PD-L1). Mechanistically, autocrine IGF2 activated PI3K/AKT signaling by binding to the IGF1 receptor (IGF1R) on CAFs, which was required for the immunosuppressive functions of CAFs. Furthermore, genetic ablation of IGF2 or targeted inhibition of the IGF2/IGF1R axis with the inhibitor linsitinib markedly boosted the response to immune checkpoint blockade. Clinically, elevated levels of IGF2 in tumors or plasma correlated with an adverse prognosis and reduced efficacy of anti-programmed death 1 treatment. Together, these results highlight the pivotal role of IGF2 in promoting CAF-mediated immunoevasion, indicating its potential as a biomarker and therapeutic target in immunotherapy.

The adipose tissue (AT) surrounding breast cancer (BC) plays a pivotal role in cancer progression and represents an optimal source for new biomarker discovery. The aim of this work was to investigate whether specific AT factors may have prognostic value in estrogen receptor-positive (ER+) BC. Proteoglycan Versican (VCAN), Insulin-like Growth Factor 1 (IGF1), Reticulon 4B (RTN4), chemokines CCL5 (also known as RANTES) and interleukin 8 (IL-8) are expressed in AT and may play important roles in BC progression. Peritumoral AT and tumoral biopsies were obtained from patients with ER+ BC (N = 23). AT specimens were collected also from healthy women (N = 17; CTRL-AT). The analysis of gene expression by qPCR revealed significantly higher mRNA levels of VCAN, IGF1, RTN4, and CCL5 in BC-AT compared to the CTRL-AT, and no difference in IL-8 mRNA levels. VCAN positively correlated with patient Body Mass Index (BMI) in BC-AT, while not in CTRL-AT. Moreover, VCAN and IGF1 positively correlated with RTN4 and negatively with CCL5. Interestingly, VCAN correlated with tumoral Ki67, while IGF1 with tumoral OCT4 that, in turn, correlated with tumoral Ki67 and patient BMI. Thus, peritumoral AT content of VCAN, and IGF1 are related to BC proliferation and aggressiveness., (© 2024. The Author(s).)

The study aimed to investigate the correlation between insulin-like growth factor 1 (IGF-1) and ocular surface parameters in obese prepubertal boys. Thirty obese prepubertal boys and 30 age- and gender-matched healthy controls underwent physical measurements, laboratory tests, and ocular surface assessments. The obese group showed lower IGF-1 levels (P = 0.001), reduced Schirmer I tear test (SIT) (P <0.001), and higher meibomian gland scores (meiboscore) compared to controls (P = 0.015). Bivariate analysis revealed a positive association between IGF-1 and SIT (r = 0.677, P < 0.001), and a negative association with between IGF-1 and meiboscore (r =  - 0.487, P < 0.001). Multiple regression analysis indicated that IGF-1 (P < 0.001) and triglycerides (P = 0.028) independently influenced SIT. Logistic analysis showed a significant association between decreased IGF-1 and higher meiboscore values (OR 0.994, 95% confidence interval 0.988-1.000; P = 0.033)., Conclusion: The findings suggest that reduced IGF-1 in obese prepubertal boys is independently linked to decreased SIT and increased meiboscore, irrespective of obesity and traditional cardiovascular risk factors. This implies that monitoring ocular surface parameters in obese children might provide a new perspective for clinical practice to focus on., What Is Known: • Obese children exhibit decreased levels of IGF-1, and this reduction in IGF-1 is associated with cardiovascular metabolic complications related to obesity. • Ocular surface tissues might act as targets for hormones, might experience local effects of these hormone., What Is New: • In prepubertal obese boys, the decrease in IGF-1 is independently linked to decreased SIT and increased meiboscore, irrespective of obesity and traditional cardiovascular risk factors. • This finding implies that monitoring ocular surface parameters in obese children might provide a new perspective for clinical practice to focus on., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Alcohol-associated liver disease(ALD), caused by excessive alcohol consumption, are often associated with inflammatory outbreaks and lipid deposition in the liver. The role of Insulin-like growth factor-binding protein 7 (IGFBP7), an important metabolic regulator, in ALD, its underlying regulatory mechanism, and its potential implication in anti-ALD therapies remain unknown. We investigated the effects of IGFBP7 on hepatic inflammation and lipid metabolism disruption in a mouse model of ALD. Mice were fed by chronic ethanol feeding plus a single binge of ethanol feeding(chronic-plus-single-binge model). In addition, ethanol exposure modeling studies were performed on cultured hepatocytes to verify molecular correlations. The results showed that IGFBP7 expression was significantly elevated in the livers of mice and hepatocytes after chronic ethanol exposure. Subsequently, the results of a study by specific knockout of IGFBP7(IGFBP7-cKO) in mouse hepatocytes and lentiviral silencing of IGFBP7 in vivo suggested that IGFBP7 deletion could improve liver function levels in alcohol-fed mice; It also attenuated the outbreak of hepatitis factor and the disorder of lipid metabolism in mice.Using RNA-seq sequencing of mouse liver tissue, we found that IGFBP7 affects several downstream metabolic signaling pathways, including PPAR, MAPK, FoxO, etc. Then, we used the PPARα plasmid in hepatocytes and discovered that overexpressing PPARα reversed the impact of IGFBP7 on lipid metabolism disorders in hepatocytes. In conclusion, IGFBP7 deficiency in alcohol-associated liver disease alleviates the decline in liver function and the imbalance of lipid metabolism in mice, attenuates the inflammatory outbreak, and affects a variety of downstream lipid metabolism factors by regulating PPARα. Hence, IGFBP7 may be an effective therapeutic target in the treatment of ALD., Competing Interests: Declaration of competing interest All authors disclosed no relevant relationships., (Copyright © 2024 Elsevier Inc. All rights reserved.)