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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 -
Nature Communications Jun 2024Tobacco smoking (TS) is implicated in lung cancer (LC) progression through the development of metabolic syndrome. However, direct evidence linking metabolic syndrome to...
Tobacco smoking (TS) is implicated in lung cancer (LC) progression through the development of metabolic syndrome. However, direct evidence linking metabolic syndrome to TS-mediated LC progression remains to be established. Our findings demonstrate that 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone and benzo[a]pyrene (NNK and BaP; NB), components of tobacco smoke, induce metabolic syndrome characteristics, particularly hyperglycemia, promoting lung cancer progression in male C57BL/6 J mice. NB enhances glucose uptake in tumor-associated macrophages by increasing the expression and surface localization of glucose transporter (GLUT) 1 and 3, thereby leading to transcriptional upregulation of insulin-like growth factor 2 (IGF2), which subsequently activates insulin receptor (IR) in LC cells in a paracrine manner, promoting its nuclear import. Nuclear IR binds to nucleophosmin (NPM1), resulting in IR/NPM1-mediated activation of the CD274 promoter and expression of programmed death ligand-1 (PD-L1). Restricting glycolysis, depleting macrophages, or blocking PD-L1 inhibits NB-mediated LC progression. Analysis of patient tissues and public databases reveals elevated levels of IGF2 and GLUT1 in tumor-associated macrophages, as well as tumoral PD-L1 and phosphorylated insulin-like growth factor 1 receptor/insulin receptor (pIGF-1R/IR) expression, suggesting potential poor prognostic biomarkers for LC patients. Our data indicate that paracrine IGF2/IR/NPM1/PD-L1 signaling, facilitated by NB-induced dysregulation of glucose levels and metabolic reprogramming of macrophages, contributes to TS-mediated LC progression.
Topics: Animals; Lung Neoplasms; Male; Humans; Mice, Inbred C57BL; Receptor, Insulin; Mice; B7-H1 Antigen; Hyperglycemia; Benzo(a)pyrene; Nucleophosmin; Insulin-Like Growth Factor II; Disease Progression; Nuclear Proteins; Nitrosamines; Tumor-Associated Macrophages; Cell Line, Tumor; Paracrine Communication; Gene Expression Regulation, Neoplastic; Smoking; Macrophages
PubMed: 38851766
DOI: 10.1038/s41467-024-49199-9 -
Nature Communications Jun 2024Mammalian inner ear hair cell loss leads to permanent hearing and balance dysfunction. In contrast to the cochlea, vestibular hair cells of the murine utricle have some...
Mammalian inner ear hair cell loss leads to permanent hearing and balance dysfunction. In contrast to the cochlea, vestibular hair cells of the murine utricle have some regenerative capacity. Whether human utricular hair cells regenerate in vivo remains unknown. Here we procured live, mature utricles from organ donors and vestibular schwannoma patients, and present a validated single-cell transcriptomic atlas at unprecedented resolution. We describe markers of 13 sensory and non-sensory cell types, with partial overlap and correlation between transcriptomes of human and mouse hair cells and supporting cells. We further uncover transcriptomes unique to hair cell precursors, which are unexpectedly 14-fold more abundant in vestibular schwannoma utricles, demonstrating the existence of ongoing regeneration in humans. Lastly, supporting cell-to-hair cell trajectory analysis revealed 5 distinct patterns of dynamic gene expression and associated pathways, including Wnt and IGF-1 signaling. Our dataset constitutes a foundational resource, accessible via a web-based interface, serving to advance knowledge of the normal and diseased human inner ear.
Topics: Humans; Transcriptome; Single-Cell Analysis; Animals; Regeneration; Mice; Saccule and Utricle; Neuroma, Acoustic; Ear, Inner; Insulin-Like Growth Factor I; Male; Hair Cells, Vestibular; Female; Gene Expression Profiling
PubMed: 38844821
DOI: 10.1038/s41467-024-48491-y -
BMC Musculoskeletal Disorders Jun 2024Osteoporosis (OS) is a systemic bone disease characterized by low bone mass and bone microstructure damage. This study.
OBJECTIVE
Osteoporosis (OS) is a systemic bone disease characterized by low bone mass and bone microstructure damage. This study.
METHODS
According to the T value, 88 elderly fracture patients were grouped as the control group (without OS, 43 cases) and observation group (with T value <-2.5, which could be diagnosed as OS, 45 cases). The content of boney containing protein (BGP), total type 1 collagen amino terminal extender peptide (TPINP), β-Crosslaps (β-CTX), parathyroid hormone (PTH) and insulin-like growth factors-1 (IGF-1) was compared. Multivariate logistic regression was adopted to analyze the correlation between biochemical indexes and the occurrence of senile OS fracture and the related risk factors. The diagnostic value in the elderly was analyzed by receiver operating characteristic (ROC) curve.
RESULTS
The levels of BGP, TPINP, β-CTX, PTH and IGF-1 were elevated, and the level of IGF-1 was decreased in the observation group compared with the control group (P < 0.05). The elevated content of BGP, TPINP, β-CTX and PTH, and the decreased expression of IGF-1 were influencing factors for OS fractures in the elderly (P < 0.05). The sensitivity and specificity to predict the occurrence of OS fractures in the elderly were 91.70% and 90.50%, respectively. The AUC of combined detection was 0.976 (95% CI: 0.952-1.000), which was memorably higher than single indicator detection (P < 0.05). Among 45 patients, 32 cases had good prognosis and 13 had poor prognosis. In comparison with the good prognosis group, the content of BGP, TPINP, β-CTX and PTH were sensibly higher, the level of IGF-1 was prominently lower, and the proportion of fracture history was much higher in poor prognosis group (P < 0.05). Fracture history, BGP, TPINP, β-CTX, PTH and IGF-1 were independent risk factors for poor prognosis of elderly OS fractures (P < 0.05).
CONCLUSION
Bone metabolism factors were associated with poor prognosis of OS in the elderly. The combined detection had higher diagnostic value in calculating the risk of OS fracture in the elderly than single indicator detection.
Topics: Humans; Aged; Female; Male; Osteoporotic Fractures; Risk Factors; Insulin-Like Growth Factor I; Aged, 80 and over; Parathyroid Hormone; Biomarkers; Osteoporosis; Predictive Value of Tests; Collagen Type I; ROC Curve; Case-Control Studies; Risk Assessment; Middle Aged
PubMed: 38840246
DOI: 10.1186/s12891-024-07560-5 -
Clinical Epigenetics Jun 2024Silver-Russell syndrome (SRS) is a representative imprinting disorder characterized by pre- and postnatal growth failure. We encountered two Japanese SRS cases with a de... (Review)
Review
Silver-Russell syndrome (SRS) is a representative imprinting disorder characterized by pre- and postnatal growth failure. We encountered two Japanese SRS cases with a de novo pathogenic frameshift variant of HMGA2 (NM_003483.6:c.138_141delinsCT, p.(Lys46Asnfs*16)) and a de novo ~ 3.4 Mb microdeletion at 12q14.2-q15 involving HMGA2, respectively. Furthermore, we compared clinical features in previously reported patients with various genetic conditions leading to compromised IGF2 expression, i.e., HMGA2 aberrations, PLAG1 aberrations, IGF2 aberrations, and H19/IGF2:IG-DMR epimutations (hypomethylations). The results provide further support for HMGA2 being involved in the development of SRS and imply some characteristic features in patients with HMGA2 aberrations.
Topics: Humans; Silver-Russell Syndrome; HMGA2 Protein; Male; Female; Frameshift Mutation; Japan; Genomic Imprinting; Infant; Insulin-Like Growth Factor II; DNA Methylation; Chromosomes, Human, Pair 12
PubMed: 38840187
DOI: 10.1186/s13148-024-01688-w -
BMC Cancer Jun 2024Circulating total insulin-like growth factor-I (IGF-I) is an established risk factor for prostate cancer. However, only a small proportion of circulating IGF-I is free...
BACKGROUND
Circulating total insulin-like growth factor-I (IGF-I) is an established risk factor for prostate cancer. However, only a small proportion of circulating IGF-I is free or readily dissociable from IGF-binding proteins (its bioavailable form), and few studies have investigated the association of circulating free IGF-I with prostate cancer risk.
METHODS
We analyzed data from 767 prostate cancer cases and 767 matched controls nested within the European Prospective Investigation into Cancer and Nutrition cohort, with an average of 14-years (interquartile range = 2.9) follow-up. Matching variables were study center, length of follow-up, age, and time of day and fasting duration at blood collection. Circulating free IGF-I concentration was measured in serum samples collected at recruitment visit (mean age 55 years old; standard deviation = 7.1) using an enzyme-linked immunosorbent assay (ELISA). Conditional logistic regressions were performed to examine the associations of free IGF-I with risk of prostate cancer overall and subdivided by time to diagnosis (≤ 14 and > 14 years), and tumor characteristics.
RESULTS
Circulating free IGF-I concentrations (in fourths and as a continuous variable) were not associated with prostate cancer risk overall (odds ratio [OR] = 1.00 per 0.1 nmol/L increment, 95% CI: 0.99, 1.02) or by time to diagnosis, or with prostate cancer subtypes, including tumor stage and histological grade.
CONCLUSIONS
Estimated circulating free IGF-I was not associated with prostate cancer risk. Further research may consider other assay methods that estimate bioavailable IGF-I to provide more insight into the well-substantiated association between circulating total IGF-I and subsequent prostate cancer risk.
Topics: Humans; Male; Prostatic Neoplasms; Insulin-Like Growth Factor I; Middle Aged; Case-Control Studies; Prospective Studies; Europe; Aged; Risk Factors; Biomarkers, Tumor; Insulin-Like Peptides
PubMed: 38831273
DOI: 10.1186/s12885-023-11425-w