-
International Journal of Molecular... May 2024Dysregulation of the insulin-like growth factor (IGF) system determines the onset of various pathological conditions, including cancer. Accordingly, therapeutic... (Review)
Review
Dysregulation of the insulin-like growth factor (IGF) system determines the onset of various pathological conditions, including cancer. Accordingly, therapeutic strategies have been developed to block this system in tumor cells, but the results of clinical trials have been disappointing. After decades of research in the field, it is safe to say that one of the major reasons underlying the poor efficacy of anti-IGF-targeting agents is derived from an underestimation of the molecular complexity of this axis. Genetic, transcriptional, post-transcriptional and functional interactors interfere with the activity of canonical components of this axis, supporting the need for combinatorial approaches to effectively block this system. In addition, cancer cells interface with a multiplicity of factors from the extracellular compartment, which strongly affect cell destiny. In this review, we will cover novel extracellular mechanisms contributing to IGF system dysregulation and the implications of such dangerous liaisons for cancer hallmarks and responses to known and new anti-IGF drugs. A deeper understanding of both the intracellular and extracellular microenvironments might provide new impetus to better decipher the complexity of the IGF axis in cancer and provide new clues for designing novel therapeutic approaches.
Topics: Humans; Neoplasms; Animals; Tumor Microenvironment; Somatomedins; Signal Transduction; Antineoplastic Agents
PubMed: 38892104
DOI: 10.3390/ijms25115915 -
International Journal of Molecular... May 2024Inflammation, demyelination, and axonal damage to the central nervous system (CNS) are the hallmarks of multiple sclerosis (MS) and its representative animal model,...
Inflammation, demyelination, and axonal damage to the central nervous system (CNS) are the hallmarks of multiple sclerosis (MS) and its representative animal model, experimental autoimmune encephalomyelitis (EAE). There is scientific evidence for the involvement of growth hormone (GH) in autoimmune regulation. Previous data on the relationship between the GH/insulin like growth factor-1 (IGF-1) axis and MS/EAE are inconclusive; therefore, the aim of our study was to investigate the changes in the GH axis during acute monophasic EAE. The results show that the gene expression of and in the hypothalamus does not change, except for and , while at the pituitary level the , and genes are upregulated. Interestingly, the cell volume of somatotropic cells in the pituitary gland remains unchanged at the peak of the disease. We found elevated serum GH levels in association with low IGF-1 concentration and downregulated and expression in the liver, indicating a condition resembling GH resistance. This is likely due to inadequate nutrient intake at the peak of the disease when inflammation in the CNS is greatest. Considering that GH secretion is finely regulated by numerous central and peripheral signals, the involvement of the GH/IGF-1 axis in MS/EAE should be thoroughly investigated for possible future therapeutic strategies, especially with a view to improving EAE disease.
Topics: Animals; Encephalomyelitis, Autoimmune, Experimental; Female; Rats; Growth Hormone; Insulin-Like Growth Factor I; Hypothalamus; Pituitary Gland; Receptors, Somatotropin; Receptors, Pituitary Hormone-Regulating Hormone; Multiple Sclerosis; Growth Hormone-Releasing Hormone; Liver; Disease Models, Animal
PubMed: 38892024
DOI: 10.3390/ijms25115837 -
International Journal of Molecular... May 2024In the majority of children with growth hormone (GH) deficiency (GHD), normal GH secretion may occur before the attainment of final height. The aim of the study was to...
Transient Isolated, Idiopathic Growth Hormone Deficiency-A Self-Limiting Pediatric Disease with Male Predominance or a Diagnosis Based on Uncertain Criteria? Lesson from 20 Years' Real-World Experience with Retesting at One Center.
In the majority of children with growth hormone (GH) deficiency (GHD), normal GH secretion may occur before the attainment of final height. The aim of the study was to assess the incidence of persistent and transient GHD and the effectiveness of recombined human GH (rhGH) therapy in children with isolated, idiopathic GHD with respect to the moment of therapy withdrawal and according to different diagnostic criteria of GHD. The analysis included 260 patients (173 boys, 87 girls) with isolated, idiopathic GHD who had completed rhGH therapy and who had been reassessed for GH and IGF-1 secretion. The incidence of transient GHD with respect to different pre- and post-treatment criteria was compared together with the assessment of GH therapy effectiveness. The incidence of transient GHD, even with respect to pediatric criteria, was very high. Normal GH secretion occurred before the attainment of near-final height. Application of more restricted criteria decreased the number of children diagnosed with GHD but not the incidence of transient GHD among them. Poor response to GH therapy was observed mainly in the patients with normal IGF-1 before treatment, suggesting that their diagnosis of GHD may have been a false positive. Further efforts should be made to avoid the overdiagnosis GHD and the overtreatment of patients.
Topics: Humans; Male; Child; Female; Human Growth Hormone; Insulin-Like Growth Factor I; Adolescent; Child, Preschool; Growth Disorders; Body Height
PubMed: 38891927
DOI: 10.3390/ijms25115739 -
International Journal of Molecular... May 2024Alzheimer's disease (AD) is characterized by the deposition in the brain of senile plaques composed of amyloid-β peptides (Aβs) that increase inflammation. An...
Reduction in Hippocampal Amyloid-β Peptide (Aβ) Content during Glycine-Proline-Glutamate (Gly-Pro-Glu) Co-Administration Is Associated with Changes in Inflammation and Insulin-like Growth Factor (IGF)-I Signaling.
Alzheimer's disease (AD) is characterized by the deposition in the brain of senile plaques composed of amyloid-β peptides (Aβs) that increase inflammation. An endogenous peptide derived from the insulin-like growth factor (IGF)-I, glycine-proline-glutamate (GPE), has IGF-I-sensitizing and neuroprotective actions. Here, we examined the effects of GPE on Aβ levels and hippocampal inflammation generated by the intracerebroventricular infusion of Aβ25-35 for 2 weeks (300 pmol/day) in ovariectomized rats and the signaling-related pathways and levels of Aβ-degrading enzymes associated with these GPE-related effects. GPE prevented the Aβ-induced increase in the phosphorylation of p38 mitogen-activated protein kinase and the reduction in activation of signal transducer and activator of transcription 3, insulin receptor substrate-1, and Akt, as well as on interleukin (IL)-2 and IL-13 levels in the hippocampus. The functionality of somatostatin, measured as the percentage of inhibition of adenylate cyclase activity and the levels of insulin-degrading enzyme, was also preserved by GPE co-treatment. These findings indicate that GPE co-administration may protect from Aβ insult by changing hippocampal cytokine content and somatostatin functionality through regulation of leptin- and IGF-I-signaling pathways that could influence the reduction in Aβ levels through modulation of levels and/or activity of Aβ proteases.
Topics: Animals; Amyloid beta-Peptides; Hippocampus; Rats; Insulin-Like Growth Factor I; Signal Transduction; Female; Oligopeptides; Inflammation; Peptide Fragments; Rats, Wistar; Alzheimer Disease; p38 Mitogen-Activated Protein Kinases; Proto-Oncogene Proteins c-akt; Insulin-Like Peptides
PubMed: 38891902
DOI: 10.3390/ijms25115716 -
Journal of Otolaryngology - Head & Neck... 2024Mesenchymal stem cells (MSCs) have the capability of providing ongoing paracrine support to degenerating tissues. Since MSCs can be extracted from a broad range of...
IMPORTANCE
Mesenchymal stem cells (MSCs) have the capability of providing ongoing paracrine support to degenerating tissues. Since MSCs can be extracted from a broad range of tissues, their specific surface marker profiles and growth factor secretions can be different. We hypothesized that MSCs derived from different sources might also have different neuroprotective potential.
OBJECTIVE
In this study, we extracted MSCs from rodent olfactory mucosa and compared their neuroprotective effects on auditory hair cell survival with MSCs extracted from rodent adipose tissue.
METHODS
Organ of Corti explants were dissected from 41 cochlea and incubated with olfactory mesenchymal stem cells (OMSCs) and adipose mesenchymal stem cells (AMSCs). After 72 hours, Corti explants were fixed, stained, and hair cells counted. Growth factor concentrations were determined in the supernatant and cell lysate using Enzyme-Linked Immunosorbent Assay (ELISA).
RESULTS
Co-culturing of organ of Corti explants with OMSCs resulted in a significant increase in inner and outer hair cell stereocilia survival, compared to control. Comparisons between both stem cell lines, showed that co-culturing with OMSCs resulted in superior inner and outer hair cell stereocilia survival rates over co-culturing with AMSCs. Assessment of growth factor secretions revealed that the OMSCs secrete significant amounts of insulin-like growth factor 1 (IGF-1). Co-culturing OMSCs with organ of Corti explants resulted in a 10-fold increase in IGF-1 level compared to control, and their secretion was 2 to 3 times higher compared to the AMSCs.
CONCLUSIONS
This study has shown that OMSCs may mitigate auditory hair cell stereocilia degeneration. Their neuroprotective effects may, at least partially, be ascribed to their enhanced IGF-1 secretory abilities compared to AMSCs.
Topics: Animals; Insulin-Like Growth Factor I; Mesenchymal Stem Cells; Rats; Hair Cells, Auditory; Olfactory Mucosa; Enzyme-Linked Immunosorbent Assay; Coculture Techniques; Cell Survival; Cells, Cultured; Adipose Tissue; Mesenchymal Stem Cell Transplantation
PubMed: 38888945
DOI: 10.1177/19160216241258431 -
Molecular Biology Reports Jun 2024Colorectal cancer (CRC) originates from pre-existing polyps in the colon. The development of different subtypes of CRC is influenced by various genetic and epigenetic...
BACKGROUND AND AIM
Colorectal cancer (CRC) originates from pre-existing polyps in the colon. The development of different subtypes of CRC is influenced by various genetic and epigenetic characteristics. CpG island methylator phenotype (CIMP) is found in about 15-20% of sporadic CRCs and is associated with hypermethylation of certain gene promoters. This study aims to find prognostic genes and compare their expression and methylation status as potential biomarkers in patients with serrated sessile adenomas/polyps (SSAP) and CRC, in order to evaluate which, one is a better predictor of disease.
METHOD
This study employed a multi-phase approach to investigate genes associated with CRC and SSAP. Initially, two gene expression datasets were analyzed using R and Limma package to identify differentially expressed genes (DEGs). Venn diagram analysis further refined the selection, revealing four genes from the Weissenberg panel with significant changes. These genes, underwent thorough in silico evaluations. Once confirmed, they proceeded to wet lab experimentation, focusing on expression and methylation status. This comprehensive methodology ensured a robust examination of the genes involved in CRC and SSAP.
RESULT
This study identified cancer-specific genes, with 8,351 and 1,769 genes specifically down-regulated in SSAP and CRC tissues, respectively. The down-regulated genes were associated with cell adhesion, negative regulation of cell proliferation, and drug response. Four highly downregulated genes in the Weissenberg panel, including CACNA1G, IGF2, MLH1, and SOCS1. In vitro analysis showed that they are hypermethylated in both SSAP and CRC samples while their expressions decreased only in CRC samples.
CONCLUSION
This suggests that the decrease in gene expression could help determine whether a polyp will become cancerous. Using both methylation status and gene expression status of genes in the Weissenberg panel in prognostic tests may lead to better prognoses for patients.
Topics: Humans; Colorectal Neoplasms; Suppressor of Cytokine Signaling 1 Protein; DNA Methylation; Insulin-Like Growth Factor II; Gene Expression Regulation, Neoplastic; MutL Protein Homolog 1; CpG Islands; Female; Colonic Polyps; Biomarkers, Tumor; Male; Down-Regulation; Computer Simulation; Middle Aged; Adenoma; Promoter Regions, Genetic; Calcium Channels, T-Type; Gene Expression Profiling; Aged; Prognosis
PubMed: 38874740
DOI: 10.1007/s11033-024-09683-3 -
Frontiers in Endocrinology 2024Prostate cancer is the second most commonly diagnosed cancer in men. The mammalian insulin-like growth factor (IGF) family is made up of three ligands (IGF-I, IGF-II,... (Review)
Review
Prostate cancer is the second most commonly diagnosed cancer in men. The mammalian insulin-like growth factor (IGF) family is made up of three ligands (IGF-I, IGF-II, and insulin), three receptors (IGF-I receptor (IGF-1R), insulin receptor (IR), and IGF-II receptor (IGF-2R)), and six IGF-binding proteins (IGFBPs). IGF-I and IGF-II were identified as potent mitogens and were previously associated with an increased risk of cancer development including prostate cancer. Several reports showed controversy about the expression of the IGF family and their connection to prostate cancer risk due to the high degree of heterogeneity among prostate tumors, sampling bias, and evaluation techniques. Despite that, it is clear that several IGF family members play a role in prostate cancer development, metastasis, and androgen-independent progression. In this review, we aim to expand our understanding of prostate tumorigenesis and regulation through the IGF system. Further understanding of the role of IGF signaling in PCa shows promise and needs to be considered in the context of a comprehensive treatment strategy.
Topics: Humans; Prostatic Neoplasms; Male; Somatomedins; Animals; Signal Transduction; Insulin-Like Growth Factor I; Insulin-Like Growth Factor Binding Proteins; Insulin-Like Peptides
PubMed: 38872970
DOI: 10.3389/fendo.2024.1396192 -
Science Advances Jun 2024The function of germ cells in somatic growth and aging has been demonstrated in invertebrate models but remains unclear in vertebrates. We demonstrated sex-dependent...
The function of germ cells in somatic growth and aging has been demonstrated in invertebrate models but remains unclear in vertebrates. We demonstrated sex-dependent somatic regulation by germ cells in the short-lived vertebrate model . In females, germ cell removal shortened life span, decreased estrogen, and increased insulin-like growth factor 1 (IGF-1) signaling. In contrast, germ cell removal in males improved their health with increased vitamin D signaling. Body size increased in both sexes but was caused by different signaling pathways, i.e., IGF-1 and vitamin D in females and males, respectively. Thus, vertebrate germ cells regulate somatic growth and aging through different pathways of the endocrine system, depending on the sex, which may underlie the sexual difference in reproductive strategies.
Topics: Animals; Germ Cells; Male; Female; Aging; Insulin-Like Growth Factor I; Vertebrates; Signal Transduction; Sex Characteristics; Body Size; Vitamin D; Estrogens
PubMed: 38865462
DOI: 10.1126/sciadv.adi1621 -
Aging Jun 2024The intermediate phase of spinal cord injury (SCI) serves as an important target site for therapeutic mediation of SCI. However, there is a lack of insight into the...
The intermediate phase of spinal cord injury (SCI) serves as an important target site for therapeutic mediation of SCI. However, there is a lack of insight into the mechanism of the intermediate phase of SCI. The present study aimed to investigate the molecular mechanism and the feasible treatment targets in the intermediate phase of SCI. We downloaded GSE2599 from GEO and identified 416 significant differentially expressed genes (DEGs), including 206 downregulated and 210 upregulated DEGs. Further enrichment analysis of DEGs revealed that many important biological processes and signal pathways were triggered in the injured spinal cord. Furthermore, a protein-protein interaction (PPI) network was constructed and the top 10 high-degree hub nodes were identified. Furthermore, 27 predicted transcription factors (TFs) and 136 predicted motifs were identified. We then selected insulin-like growth factor 1 (IGF1) and its predicted transcription factor, transcription factor A, mitochondrial (TFAM) for further investigation. We speculated and preliminarily confirmed that TFAM may regulate gene transcription of IGF1 and effected alterations in the function recovery of rats after SCI. These findings together provide novel information that may improve our understanding of the pathophysiological processes during the intermediate phase of SCI.
Topics: Animals; Spinal Cord Injuries; Rats; Transcription Factors; Insulin-Like Growth Factor I; Protein Interaction Maps; Gene Expression Profiling; Spinal Cord; DNA-Binding Proteins; Gene Regulatory Networks; Rats, Sprague-Dawley; Gene Expression Regulation; Mitochondrial Proteins
PubMed: 38862258
DOI: 10.18632/aging.205912 -
Proceedings of the National Academy of... Jun 2024Ciliary defects are linked to ciliopathies, but impairments in the sensory cilia of neurons extend lifespan, a phenomenon with previously unclear mechanisms. Our study...
Ciliary defects are linked to ciliopathies, but impairments in the sensory cilia of neurons extend lifespan, a phenomenon with previously unclear mechanisms. Our study reveals that neuronal cilia defects trigger the unfolded protein response of the endoplasmic reticulum (UPR) within intestinal cells, a process dependent on the insulin/insulin-like growth factor 1 (IGF-1) signaling transcription factor and the release of neuronal signaling molecules. While inhibiting UPR doesn't alter the lifespan of wild-type worms, it normalizes the extended lifespan of ciliary mutants. Notably, deactivating the cyclic nucleotide-gated (CNG) channel TAX-4 on the ciliary membrane promotes lifespan extension through a UPR-dependent mechanism. Conversely, constitutive activation of TAX-4 attenuates intestinal UPR in ciliary mutants. Administering a CNG channel blocker to worm larvae activates intestinal UPR and increases adult longevity. These findings suggest that ciliary dysfunction in sensory neurons triggers intestinal UPR, contributing to lifespan extension and implying that transiently inhibiting ciliary channel activity may effectively prolong lifespan.
Topics: Animals; Caenorhabditis elegans; Unfolded Protein Response; Cilia; Longevity; Caenorhabditis elegans Proteins; Cyclic Nucleotide-Gated Cation Channels; Intestines; Signal Transduction; Neurons; Endoplasmic Reticulum; Insulin-Like Growth Factor I; Intestinal Mucosa
PubMed: 38857399
DOI: 10.1073/pnas.2321228121