Insulin-like Growth Factor Signaling Research Articles

The microbiome: a link between obesity and breast cancer risk

Globally, breast cancer is the leading cause of cancer incidence and mortality among all female cancers. Hereditary factors only account for 5-10% of breast cancers, highlighting the importance of non-hereditary factors, such as obesity. The increasing prevalence of obesity underscores the need to understand its contribution to breast cancer risk. Multiple mechanisms may mediate pro-carcinogenic effects of obesity, including altered adipokine levels, local and systemic inflammation, disruption of insulin and insulin-like growth factor signaling, increased estrogen levels, and alterations of the microbiome. In this review, we focus on the link between gut microbiome alterations and breast cancer risk in the context of obesity. First, we discuss how obesity influences the gut microbiome. Next, we describe the effect of such microbiome alterations on breast carcinogenesis, highlighting underlying molecular mechanisms. Finally, we review preclinical data on the interactions between host and bacteria, current challenges to study the obesity-microbiome connection, and future perspectives in this field.

Protein intake and cancer: an umbrella review of systematic reviews for the evidence-based guideline of the German Nutrition Society.

It has been proposed that a higher habitual protein intake may increase cancer risk, possibly via upregulated insulin-like growth factor signalling. Since a systematic evaluation of human studies on protein intake and cancer risk based on a standardised assessment of systematic reviews (SRs) is lacking, we carried out an umbrella review of SRs on protein intake in relation to risks of different types of cancer. Following a pre-specified protocol (PROSPERO: CRD42018082395), we retrieved SRs on protein intake and cancer risk published before January 22th 2024, and assessed the methodological quality and outcome-specific certainty of the evidence using a modified version of AMSTAR 2 and NutriGrade, respectively. The overall certainty of evidence was rated according to predefined criteria. Ten SRs were identified, of which eight included meta-analyses. Higher total protein intake was not associated with risks of breast, prostate, colorectal, ovarian, or pancreatic cancer incidence. The methodological quality of the included SRs ranged from critically low (kidney cancer), low (pancreatic, ovarian and prostate cancer) and moderate (breast and prostate cancer) to high (colorectal cancer). The outcome-specific certainty of the evidence underlying the reported findings on protein intake and cancer risk ranged from very low (pancreatic, ovarian and prostate cancer) to low (colorectal, ovarian, prostate, and breast cancer). Animal and plant protein intakes were not associated with cancer risks either at a low (breast and prostate cancer) or very low (pancreatic and prostate cancer) outcome-specific certainty of the evidence. Overall, the evidence for the lack of an association between protein intake and (i) colorectal cancer risk and (ii) breast cancer risk was rated as possible. By contrast, the evidence underlying the other reported results was rated as insufficient. The present findings suggest that higher total protein intake may not be associated with the risk of colorectal and breast cancer, while conclusions on protein intake in relation to risks of other types of cancer are restricted due to insufficient evidence.

Role of the Insulin-like Growth Factor System in Neurodegenerative Disease.

The insulin-like growth factor (IGF) system has paracrine and endocrine roles in the central nervous system. There is evidence that IGF signalling pathways have roles in the pathophysiology of neurodegenerative disease. This review focusses on Alzheimer's disease and Parkinson's disease, the two most common neurodegenerative disorders that are increasing in prevalence globally in relation to the aging population and the increasing prevalence of obesity and type 2 diabetes. Rodent models used in the study of the molecular pathways involved in neurodegeneration are described. However, currently, no animal model fully replicates these diseases. Mice with triple mutations in APP, PSEN and MAPT show promise as models for the testing of novel Alzheimer's therapies. While a causal relationship is not proven, the fact that age, obesity and T2D are risk factors in both strengthens the case for the involvement of the IGF system in these disorders. The IGF system is an attractive target for new approaches to management; however, there are gaps in our understanding that first need to be addressed. These include a focus beyond IGF-I on other members of the IGF system, including IGF-II, IGF-binding proteins and the type 2 IGF receptor.

Omental preadipocytes stimulate matrix remodeling and IGF signaling to support ovarian cancer metastasis.

Ovarian cancer can metastasize to the omentum, which is associated with a complex tumor microenvironment. Omental stromal cells facilitate ovarian cancer colonization by secreting cytokines and growth factors. Improved understanding of the tumor supportive functions of specific cell populations in the omentum could identify strategies to prevent and treat ovarian cancer metastasis. Here, we showed that omental preadipocytes enhance the tumor initiation capacity of ovarian cancer cells. Secreted factors from preadipocytes supported cancer cell viability during nutrient and isolation stress and enabled prolonged proliferation. Co-culturing with pre-adipocytes led to upregulation of genes involved in extracellular matrix (ECM) organization, cellular response to stress, and regulation of insulin-like growth factor (IGF) signaling in ovarian cancer cells. IGF-1 induced ECM genes and increased alternative NF-κB signaling by activating RelB. Inhibiting the IGF-1 receptor (IGF1R) initially increased tumor omental adhesion but decreased growth of established preadipocyte-induced subcutaneous tumors as well as established intraperitoneal tumors. Together, this study shows that omental preadipocytes support ovarian cancer progression, which has implications for targeting metastasis.

Antioxidant and anti-aging activities of Longan crude and purified polysaccharide (LP-A) in nematode Caenorhabditis elegans

Oxidative damage is an important cause of aging. The antioxidant and anti-aging activities of Longan polysaccharides, especially purified Longan polysaccharides, have not been thoroughly investigated. Therefore, this study aimed to investigate the antioxidant and anti-aging activities and mechanisms of crude polysaccharides and purified polysaccharides from Longan. A purified acidic Longan polysaccharide LP-A was separated from Longan crude polysaccharide LP. Subsequently, its structural characterization, anti-aging activity and mechanism were studied. The results showed that LP-A was an acidic heteropolysaccharide with an average molecular weight (Mw) of 4.606 × 104 Da which was composed of nine monosaccharides. The scavenging rate of ABTS free radical in vitro reached 99 %. In the nematode life experiment, 0.3 mg/mL LP group and LP-A group could prolong the average lifespan of nematodes by 9.31 % and 25.80 %, respectively. Under oxidative stress stimulation, LP-A group could prolong the survival time of nematodes by 69.57 %. In terms of mechanism, Longan polysaccharide can regulate insulin / insulin-like growth factor (IIS) signaling pathway, increase the activity of antioxidant enzymes, reduce lipid peroxidation, enhance the body's resistance to stress damage, and effectively prolong the lifespan of nematodes. In conclusion, LP-A has better anti-aging activity than crude polysaccharide LP, which has great potential for developing as an anti-aging drug.

Insulin Signaling Differentially Regulates the Trafficking of Insulin and Amyloid Beta Peptides at the Blood-Brain Barrier.

The blood-brain barrier (BBB) is instrumental in clearing toxic metabolites from the brain, such as amyloid-β (Aβ) peptides, and in delivering essential nutrients to the brain, like insulin. In Alzheimer's disease (AD) brain, increased Aβ levels are paralleled by decreased insulin levels, which are accompanied by insulin signaling deficits at the BBB. Thus, we investigated the impact of insulin-like growth factor and insulin receptor (IGF1R and IR) signaling on Aβ and insulin trafficking at the BBB. Following intravenous infusion of an IGF1R/IR kinase inhibitor (AG1024) in wild-type mice, the BBB trafficking of 125I radiolabeled Aβ peptides and insulin was assessed by dynamic SPECT/CT imaging. The brain efflux of [125I]iodo-Aβ42 decreased upon AG1024 treatment. Additionally, the brain influx of [125I]iodoinsulin, [125I]iodo-Aβ42, [125I]iodo-Aβ40, and [125I]iodo-BSA (BBB integrity marker) was decreased, increased, unchanged, and unchanged, respectively, upon AG1024 treatment. Subsequent mechanistic studies were performed using an in vitro BBB cell model. The cell uptake of [125I]iodoinsulin, [125I]iodo-Aβ42, and [125I]iodo-Aβ40 was decreased, increased, and unchanged, respectively, upon AG1024 treatment. Further, AG1024 reduced the phosphorylation of insulin signaling kinases (Akt and Erk) and the membrane expression of Aβ and insulin trafficking receptors (LRP-1 and IR-β). These findings reveal that insulin signaling differentially regulates the BBB trafficking of Aβ peptides and insulin. Moreover, deficits in IGF1R and IR signaling, as observed in the brains of type II diabetes and AD patients, are expected to increase Aβ accumulation while decreasing insulin delivery to the brain, which has been linked to the progression of cognitive decline in AD.

Sex-based differences in growth-related IGF1 signaling in response to PAPP-A2 deficiency: comparative effects of rhGH, rhIGF1 and rhPAPP-A2 treatments

BackgroundChildren with pregnancy-associated plasma protein-A2 (PAPP-A2) mutations resulting in low levels of bioactive insulin-like growth factor-1 (IGF1) and progressive postnatal growth retardation have improved growth velocity and height following recombinant human (rh)IGF1 treatment. The present study aimed to evaluate whether Pappa2 deficiency and pharmacological manipulation of GH/IGF1 system are associated with sex-specific differences in growth-related signaling pathways.MethodsPlasma, hypothalamus, pituitary gland and liver of Pappa2ko/ko mice of both sexes, showing reduced skeletal growth, and liver of these mice treated with rhGH, rhIGF1 and rhPAPP-A2 from postnatal day (PND) 5 to PND35 were analyzed.ResultsReduced body and femur length of Pappa2ko/ko mice was associated with increases in: (1) components of IGF1 ternary complexes (IGF1, IGFBP5/Igfbp5, Igfbp3, Igfals) in plasma, hypothalamus and/or liver; and (2) key signaling regulators (phosphorylated PI3K, AKT, mTOR, GSK3β, ERK1/2 and AMPKα) in hypothalamus, pituitary gland and/or liver, with Pappa2ko/ko females having a more prominent effect. Compared to rhGH and rhIGF1, rhPAPP-A2 specifically induced: (1) increased body and femur length, and reduced plasma total IGF1 and IGFBP5 concentrations in Pappa2ko/ko females; and (2) increased Igf1 and Igf1r levels and decreased Ghr, Igfbp3 and Igfals levels in the liver of Pappa2ko/ko females. These changes were accompanied by lower phospho-STAT5, phospho-AKT and phospho-ERK2 levels and higher phospho-AMPK levels in the liver of Pappa2ko/ko females.ConclusionsSex-specific differences in IGF1 system and signaling pathways are associated with Pappa2 deficiency, pointing to rhPAPP-A2 as a promising drug to alleviate postnatal growth retardation underlying low IGF1 bioavailability in a female-specific manner.

[Regulation of Aging Processes: A Perspective of Dietary Restriction Models].

The moderate restriction of dietary energy intake (dietary restriction: DR) extends the lifespan and health span of various laboratory animals, suggesting that it delays the aging process inherent in many animal species. Attenuated growth hormone and insulin-like growth factor-1 (IGF-1) signaling caused by mutations also increases the lifespan of mice, even those allowed to feed freely. In nematodes, the Daf16, mammalian Forkhead box O (FoxO) transcription factor, was shown to be required for lifespan extension in response to reduced IGF-1 signaling. Because DR also decreases the plasma concentration of IGF-1 in mammals, the IGF-1-FoxO axis may play a central role in the lifespan extension effect of DR and, thus, retardation of aging. Studies using knockout mice under DR conditions revealed the importance of FoxO1 and nuclear factor erythroid-derived 2-like 2 (Nrf2) in tumor suppression, and FoxO3 in lifespan extension. Human genomic studies also identified a strong association between a FOXO3 single nucleotide polymorphism and longevity. The aging mechanism is the most important risk factor for disease and frailty in aging humans. Therefore, further research on the application of DR to humans, the development of compounds and drugs that mimic the effects of DR, and mechanisms underlying FOXO3 polymorphisms for longevity is highly relevant to extending the human health span.

Ex Vivo Culture of Circulating Tumor Cells in the Cerebral Spinal Fluid from Melanoma Patients to Study Melanoma-Associated Leptomeningeal Disease.

Melanoma-associated leptomeningeal disease (M-LMD) occurs when circulating tumor cells (CTCs) enter into the cerebral spinal fluid (CSF) and colonize the meninges, the membrane layers that protect the brain and the spinal cord. Once established, the prognosis for M-LMD patients is dismal, with overall survival ranging from weeks to months. This is primarily due to a paucity in our understanding of the disease and, as a consequence, the availability of effective treatment options. Defining the underlying biology of M-LMD will significantly improve the ability to adapt available therapies for M-LMD treatment or design novel inhibitors for this universally fatal disease. A major barrier, however, lies in obtaining sufficient quantities of CTCs from the patient-derived CSF (CSF-CTCs) to conduct preclinical experiments, such as molecular characterization, functional analysis, and in vivo efficacy studies. Culturing CSF-CTCs ex vivo has also proven to be challenging. To address this, a novel protocol for the culture of patient-derived M-LMD CSF-CTCs ex vivo and in vivo is developed. The incorporation of conditioned media produced by human meningeal cells (HMCs) is found to be critical to the procedure. Cytokine array analysis reveals that factors produced by HMCs, such as insulin-like growth factor-binding proteins (IGFBPs) and vascular endothelial growth factor-A (VEGF-A), are important in supporting CSF-CTC survival ex vivo. Here, the usefulness of the isolated patient-derived CSF-CTC lines is demonstrated in determining the efficacy of inhibitors that target the insulin-like growth factor (IGF) and mitogen-activated protein kinase (MAPK) signaling pathways. In addition, the ability to intrathecally inoculate these cells in vivo to establish murine models of M-LMD that can be employed for preclinical testing of approved or novel therapies is shown. These tools can help unravel the underlying biology driving CSF-CTC establishment in the meninges and identify novel therapies to reduce the morbidity and mortality associated with M-LMD.

Apelin regulates skeletal muscle adaptation to exercise in a high-intensity interval training model.

Plasma apelin levels are reduced in aging and muscle wasting conditions. We aimed to investigate the significance of apelin signaling in cardiac and skeletal muscle responses to physiological stress. Apelin knockout (KO) and wild-type (WT) mice were subjected to high-intensity interval training (HIIT) by treadmill running. The effects of apelin on energy metabolism were studied in primary mouse skeletal muscle myotubes and cardiomyocytes. Apelin increased mitochondrial ATP production and mitochondrial coupling efficiency in myotubes and promoted the expression of mitochondrial genes both in primary myotubes and cardiomyocytes. HIIT induced mild concentric cardiac hypertrophy in WT mice, whereas eccentric growth was observed in the left ventricles of apelin KO mice. HIIT did not affect myofiber size in skeletal muscles of WT mice but decreased the myofiber size in apelin KO mice. The decrease in myofiber size resulted from a fiber type switch toward smaller slow-twitch type I fibers. The increased proportion of slow-twitch type I fibers in apelin KO mice was associated with upregulation of myosin heavy chain slow isoform expression, accompanied with upregulated expression of genes related to fatty acid transport and downregulated expression of genes related to glucose metabolism. Mechanistically, skeletal muscles of apelin KO mice showed defective induction of insulin-like growth factor-1 signaling in response to HIIT. In conclusion, apelin is required for proper skeletal and cardiac muscle adaptation to high-intensity exercise. Promoting apelinergic signaling may have benefits in aging- or disease-related muscle wasting conditions.NEW & NOTEWORTHY Apelin levels decline with age. This study demonstrates that in trained mice, apelin deficiency results in a switch from fast type II myofibers to slow oxidative type I myofibers. This is associated with a concomitant change in gene expression profile toward fatty acid utilization, indicating an aged-muscle phenotype in exercised apelin-deficient mice. These data are of importance in the design of exercise programs for aging individuals and could offer therapeutic target to maintain muscle mass.

Network visualization of genes involved in skeletal muscle myogenesis in livestock animals

BackgroundMuscle growth post-birth relies on muscle fiber number and size. Myofibre number, metabolic and contractile capacities are established pre-birth during prenatal myogenesis. The aim of this study was to identify genes involved in skeletal muscle development in cattle, sheep, and pigs - livestock.ResultsThe cattle analysis showed significant differences in 5043 genes during the 135–280 dpc period. In sheep, 444 genes differed significantly during the 70–120 dpc period. Pigs had 905 significantly different genes for the 63–91 dpc period.The biological processes and KEGG pathway enrichment results in each species individually indicated that DEGs in cattle were significantly enriched in regulation of cell proliferation, cell division, focal adhesion, ECM-receptor interaction, and signaling pathways (PI3K-Akt, PPAR, MAPK, AMPK, Ras, Rap1); in sheep - positive regulation of fibroblast proliferation, negative regulation of endothelial cell proliferation, focal adhesion, ECM-receptor interaction, insulin resistance, and signaling pathways (PI3K-Akt, HIF-1, prolactin, Rap1, PPAR); in pigs - regulation of striated muscle tissue development, collagen fibril organization, positive regulation of insulin secretion, focal adhesion, ECM-receptor interaction, and signaling pathways (PPAR, FoxO, HIF-1, AMPK). Among the DEGs common for studied animal species, 45 common genes were identified. Based on these, a protein-protein interaction network was created and three significant modules critical for skeletal muscle myogenesis were found, with the most significant module A containing four recognized hub genes - EGFR, VEGFA, CDH1, and CAV1. Using the miRWALK and TF2DNA databases, miRNAs (bta-miR-2374 and bta-miR-744) and transcription factors (CEBPB, KLF15, RELA, ZNF143, ZBTB48, and REST) associated with hub genes were detected. Analysis of GO term and KEGG pathways showed that such processes are related to myogenesis and associated with module A: positive regulation of MAP kinase activity, vascular endothelial growth factor receptor, insulin-like growth factor binding, focal adhesion, and signaling pathways (PI3K-Akt, HIF-1, Rap1, Ras, MAPK).ConclusionsThe identified genes, common to the prenatal developmental period of skeletal muscle in livestock, are critical for later muscle development, including its growth by hypertrophy. They regulate valuable economic characteristics. Enhancing and breeding animals according to the recognized genes seems essential for breeders to achieve superior gains in high-quality muscle mass.

Single cell atlas of kidney cancer endothelial cells reveals distinct expression profiles and phenotypes

BackgroundTumor endothelial cells (TECs) represent the primary interface between the tumor microenvironment and circulating immune cells, however their phenotypes are incompletely understood in highly vascularized clear cell renal cell carcinoma (ccRCC).MethodsWe purified tumor and matched normal endothelial cells (NECs) from ccRCC specimens and performed single-cell RNA-sequencing to create a reference-quality atlas available as a searchable web resource for gene expression patterns. We established paired primary TECs and NECs cultures for ex vivo functional testing.ResultsTECs from multiple donors shared a common phenotype with increased expression of pathways related to extracellular matrix regulation, cell-cell communication, and insulin-like growth factor signaling. This phenotype was shared with hepatocellular carcinoma associated TECs, suggesting convergent TEC phenotypes between unrelated tumors. Cultured TECs stably maintained a core program of differentially regulated genes which promoted resistance to apoptosis after vascular endothelial growth factor removal and increased adhesiveness to subsets of immune cells including regulatory T-cells.ConclusionsOur studies demonstrate that TECs have a distinct phenotype that is shared by TECs from different tumor types and stable in ex vivo culture. The distinct adhesive interaction of TECs with immune cells raises the possibility of their modulation to improve immune cell-based therapies for RCC.

Antisense Oligonucleotide-Mediated Downregulation of IGFBPs Enhances IGF-1 Signaling.

Insulin-like growth factor-1 (IGF-1) has been considered as a therapeutic agent for muscle wasting conditions including Duchenne muscular dystrophy as it stimulates muscle regeneration, growth and function. Several preclinical and clinical studies have been conducted to show the therapeutic potential of IGF-1, however, delivery issues, short half-life and isoform complexity have impose challenges. Antisense oligonucleotides (AONs) are able to downregulate target proteins by interfering with their transcripts. Here, we investigated the feasibility of enhancing IGF-1 signaling by downregulation of IGF-binding proteins. We observed that out of frame exon skipping of Igfbp1 and Igfbp3 downregulated their protein expression, which increased Akt phosphorylation on the downstream IGF-1 signaling in vitro. 3'RNA sequencing analysis revealed the related transcriptome in C2C12 cells in response to IGFBP3 downregulation. The AONs did however not induce any exon skipping or protein knockdown in mdx mice after 6 weeks of systemic treatment. We conclude that IGFBP downregulation could be a good strategy to increase IGF-1 signaling but alternative tools are needed for efficient delivery and knockdown in vivo.

Prenatal prednisone exposure impacts liver development and function in fetal mice and its characteristics.

Prednisone, a widely used glucocorticoid drug in human and veterinary medicine, has been reported to cause developmental toxicity. However, systematic studies about the effect of prednisone on fetal liver development are still unclear. We investigated the potential effects of maternal exposure to clinically equivalent doses of prednisone during different gestational stages on cell proliferation and apoptosis, cell differentiation, glucose and lipid metabolism, and hematopoiesis in the liver of fetal mice, and explored the potential mechanisms. Results showed that prenatal prednisone exposure (PPE) could suppress the cell proliferation, inhibit hepatocyte differentiation and promote cholangiocyte differentiation in fetal liver. Meanwhile, PPE could result in the enhancement of glyconeogenesis and bile acid synthesis and the inhibition of fatty acid β-oxidation and hematopoiesis in fetal liver. Further analysis found that PPE-induced alterations in liver development had obvious stage- and sex-differences. Overall, the alteration in fetal liver development and function induced by PPE was most pronounced during the whole pregnancy (GD0-10), and the males were relatively more affected than the females. Additionally, fetal hepatic insulin-like growth factor 1 (IGF1) signaling pathway was inhibited by PPE. In conclusion, PPE could impact fetal liver development and multiple functions, and these alterations might be partially related to the inhibition of IGF1 signaling pathway.

Abstract B078: Insulin-like growth factor signaling contributes to omental preadipocyte-mediated tumorigenesis in ovarian cancer by regulating expression of extracellular matrix genes

Abstract B078: Insulin-like growth factor signaling contributes to omental preadipocyte-mediated tumorigenesis in ovarian cancer by regulating expression of extracellular matrix genes

Longitudinal analysis of host protein serum signatures of treatment and recovery in pulmonary tuberculosis.

A better understanding of treatment progression and recovery in pulmonary tuberculosis (TB) infectious disease is crucial. This study analyzed longitudinal serum samples from pulmonary TB patients undergoing interventional treatment to identify surrogate markers for TB-related outcomes. Serum that was collected at baseline and 8, 17, 26, and 52 weeks from 30 TB patients experiencing durable cure were evaluated and compared using a sensitive LC-MS/MS proteomic platform for the detection and quantification of differential host protein signatures relative to timepoint. The global proteome signature was analyzed for statistical differences across the time course and between disease severity and treatment groups. A total of 676 proteins showed differential expression in the serum over these timepoints relative to baseline. Comparisons to understand serum protein dynamics at 8 weeks, treatment endpoints at 17 and 26 weeks, and post-treatment at 52 weeks were performed. The largest protein abundance changes were observed at 8 weeks as the initial effects of antibiotic treatment strongly impacted inflammatory and immune modulated responses. However, the largest number of proteome changes was observed at the end of treatment time points 17 and 26 weeks respectively. Post-treatment 52-week results showed an abatement of differential proteome signatures from end of treatment, though interestingly those proteins uniquely significant at post-treatment were almost exclusively downregulated. Patients were additionally stratified based upon disease severity and compared across all timepoints, identifying 461 discriminating proteome signatures. These proteome signatures collapsed into discrete expression profiles with distinct pathways across immune activation and signaling, hemostasis, and metabolism annotations. Insulin-like growth factor (IGF) and Integrin signaling maintained a severity signature through 52 weeks, implying an intrinsic disease severity signature well into the post-treatment timeframe. Previous proteome studies have primarily focused on the 8-week timepoint in relation to culture conversion status. While this study confirms previous observations, it also highlights some differences. The inclusion of additional end of treatment and post-treatment time points offers a more comprehensive assessment of treatment progression within the serum proteome. Examining the expression dynamics at these later time periods will help in the investigation of relapse patients and has provided indicative markers of response and recovery.

Vascular smooth muscle cell-specific Igf1r deficiency exacerbates the development of hypertension-induced cerebral microhemorrhages and gait defects.

Cerebrovascular fragility and cerebral microhemorrhages (CMH) contribute to age-related cognitive impairment, mobility defects, and vascular cognitive impairment and dementia, impairing healthspan and reducing quality of life in the elderly. Insulin-like growth factor 1 (IGF-1) is a key vasoprotective growth factor that is reduced during aging. Circulating IGF-1 deficiency leads to the development of CMH and other signs of cerebrovascular dysfunction. Here our goal was to understand the contribution of IGF-1 signaling on vascular smooth muscle cells (VSMCs) to the development of CMH and associated gait defects. We used an inducible VSMC-specific promoter and an IGF-1 receptor (Igf1r) floxed mouse line (Myh11-CreERT2 Igf1rf/f) to knockdown Igf1r. Angiotensin II in combination with L-NAME-induced hypertension was used to elicit CMH. We observed that VSMC-specific Igf1r knockdown mice had accelerated development of CMH, and subsequent associated gait irregularities. These phenotypes were accompanied by upregulation of a cluster of pro-inflammatory genes associated with VSMC maladaptation. Collectively our findings support an essential role for VSMCs as a target for the vasoprotective effects of IGF-1, and suggest that VSMC dysfunction in aging may contribute to the development of CMH.

Multi-omics analysis revealed the dysfunction of ovary and testis induced by chronic hypoxia in Pelteobagrus fulvidraco

Hypoxia is a global problem that not only impairs parental fish reproductive functions and fertility but can also decrease offspring fertility through the transgenerational effect, further resulting in the degradation of fish germplasm resources in aquaculture. However, an in-depth exploration of the comprehensive mechanisms of hypoxia-induced gonadal impairment in teleosts is lacking. In this study, the juvenile yellow catfish (Pelteobagrus fulvidraco) were continuously exposed to hypoxic conditions (1.9 ± 0.3 mg/L dissolved oxygen) for one month. The transcriptome, proteome, and metabolome were integrated to study the gonadal response to hypoxia in yellow catfish comprehensively. Hypoxia altered gonadal biological processes involved in angiogenesis, energy metabolism, apoptosis, and steroidogenesis. The testes and ovaries exhibited different adaptive mechanisms in response to chronic hypoxia. Angiogenesis was activated in the testes to increase oxygen delivery. Angiogenesis was inhibited in the ovaries when ovarian hemoglobin levels increased. Activated glycolysis and catabolism of glycogenic amino acids were observed in the testes. The energy metabolism in the ovaries was disrupted by hypoxia, as reflected by disordered glycolysis and suppressed synthesis of amino acids and fatty acids. Gonadal dysfunction and suppression of germ cell development by hypoxia were observed. The decrease in synaptonemal complex protein 1 (SYCP1), SYCP3, Piwi like RNA-mediated gene silencing 2 (PIWIL2), and Nanos C2HC-type zinc finger 3 (Nanos3) in the testes reflected suppressed meiosis and spermatogenesis. The downregulation of vitellogenin 1 (VTG1), zona pellucida (ZP), growth differentiation factor 9 (GDF9), inhibin subunit beta B (Inhbb), and insulin-like growth factor (IGF) signaling inhibited folliculogenesis and vitellogenesis in the ovaries. Our results provide insight into the molecular mechanisms underlying hypoxia-induced reproductive impairment in teleosts.

C. elegans insulin-like peptides

Insulin-like peptides are a group of hormones crucial for regulating metabolism, growth, and development in animals. Invertebrates, such as C. elegans, have been instrumental in understanding the molecular mechanisms of insulin-like peptides. Here, we review the 40 insulin-like peptide genes encoded in the C. elegans genome. Despite the large number, there is only one C. elegans insulin-like peptide receptor, called DAF-2. The insulin and insulin-like growth factor signaling (IIS) pathway is evolutionarily conserved from worms to humans. Thus C. elegans provides an excellent model to understand how these insulin-like peptides function. C. elegans is unique in that it possesses insulin-like peptides that have antagonistic properties, unlike all human insulin-like peptides, which are agonists. This review provides an overview of the current literature on C. elegans insulin-like peptide structures, processing, tissue localization, and regulation. We will also provide examples of insulin-like peptide signaling in C. elegans during growth, development, germline development, learning/memory, and longevity.

Investigating the clinical role and prognostic value of genes related to insulin-like growth factor signaling pathway in thyroid cancer.

Thyroid cancer (THCA) is the most common endocrine malignancy having a female predominance. The insulin-like growth factor (IGF) pathway contributed to the unregulated cell proliferation in multiple malignancies. We aimed to explore the IGF-related signature for THCA prognosis. The TCGA-THCA dataset was collected from the Cancer Genome Atlas (TCGA) for screening of key prognostic genes. The limma R package was applied for differentially expressed genes (DEGs) and the clusterProfiler R package was used for the Gene Ontology (GO) and KEGG analysis of DEGs. Then, the un/multivariate and least absolute shrinkage and selection operator (Lasso) Cox regression analysis was used for the establishment of RiskScore model. Receiver Operating Characteristic (ROC) analysis was used to verify the model's predictive performance. CIBERSORT and MCP-counter algorithms were applied for immune infiltration analysis. Finally, we analyzed the mutation features and the correlation between the RiskScore and cancer hallmark pathway by using the GSEA. We obtained 5 key RiskScore model genes for patient's risk stratification from the 721 DEGs. ROC analysis indicated that our model is an ideal classifier, the high-risk patients are associated with the poor prognosis, immune infiltration, high tumor mutation burden (TMB), stronger cancer stemness and stronger correlation with the typical cancer-activation pathways. A nomogram combined with multiple clinical features was developed and exhibited excellent performance upon long-term survival quantitative prediction. We constructed an excellent prognostic model RiskScore based on IGF-related signature and concluded that the IGF signal pathway may become a reliable prognostic phenotype in THCA intervention.