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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 -
Science Translational Medicine Jun 2024Clinical evidence indicates a close association between muscle dysfunction and bone loss; however, the underlying mechanisms remain unclear. Here, we report that muscle...
Clinical evidence indicates a close association between muscle dysfunction and bone loss; however, the underlying mechanisms remain unclear. Here, we report that muscle dysfunction-related bone loss in humans with limb-girdle muscular dystrophy is associated with decreased expression of folliculin-interacting protein 1 (FNIP1) in muscle tissue. Supporting this finding, murine gain- and loss-of-function genetic models demonstrated that muscle-specific ablation of FNIP1 caused decreased bone mass, increased osteoclastic activity, and mechanical impairment that could be rescued by myofiber-specific expression of FNIP1. Myofiber-specific FNIP1 deficiency stimulated expression of nuclear translocation of transcription factor EB, thereby activating transcription of insulin-like growth factor 2 () at a conserved promoter-binding site and subsequent IGF2 secretion. Muscle-derived IGF2 stimulated osteoclastogenesis through IGF2 receptor signaling. AAV9-mediated overexpression of IGF2 was sufficient to decrease bone volume and impair bone mechanical properties in mice. Further, we found that serum IGF2 concentration was negatively correlated with bone health in humans in the context of osteoporosis. Our findings elucidate a muscle-bone cross-talk mechanism bridging the gap between muscle dysfunction and bone loss. This cross-talk represents a potential target to treat musculoskeletal diseases and osteoporosis.
Topics: Animals; Female; Humans; Male; Mice; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; Bone and Bones; Insulin-Like Growth Factor II; Muscle, Skeletal; Muscles; Osteoclasts; Osteogenesis; Signal Transduction
PubMed: 38838134
DOI: 10.1126/scitranslmed.adk9811 -
Reproduction in Domestic Animals =... Jun 2024This study aims to investigate the relationship between metabolic parameters and the number of embryos produced in superovulated cows with high genetic characteristics...
This study aims to investigate the relationship between metabolic parameters and the number of embryos produced in superovulated cows with high genetic characteristics in milk yield. Eighteen Holstein donors were treated with classic superovulation protocols, AI and flushing. During superovulation, decreasing doses of FSH (follicle-stimulating hormone) were administered at 12-h intervals for 4 days. Plasma insulin-like growth factor (IGF1), glucose (GLU), beta-hydroxybutyric acid (BHB), non-esterified fatty acid (NEFA), blood urea nitrogen (BUN) and total protein (TP) levels were determined by using an autoanalyzer. The mixed model analysis of variance was used for statistical analysis. As a result, plasma IGF1, BHB and BUN had significant interactions with both groups and days (p < .05). Additionally, plasma TP-days interactions were significant (p < .05). Furthermore, there was a negative correlation between the number of embryos and plasma BHB levels (p < .05). In conclusion, under appropriate environmental conditions, metabolic profile control of donors can contribute to the embryo production process and to the studies on the metabolic infrastructure.
Topics: Animals; Cattle; Superovulation; Female; 3-Hydroxybutyric Acid; Fatty Acids, Nonesterified; Follicle Stimulating Hormone; Insulin-Like Growth Factor I; Blood Glucose; Blood Urea Nitrogen; Insemination, Artificial; Pregnancy
PubMed: 38837288
DOI: 10.1111/rda.14629 -
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 -
International Journal of Biological... Jun 2024Injectable hydrogels, offering adaptable drug delivery of growth factors (GFs), hold promise for treating bone defects. To optimize osteogenic efficacy, the release of...
Injectable hydrogels, offering adaptable drug delivery of growth factors (GFs), hold promise for treating bone defects. To optimize osteogenic efficacy, the release of GFs should mirror the natural bone healing. We developed an injectable thermo-responsive hydrogel/microgels platform for dual GF delivery for bone regeneration. Stromal cell-derived factor-1 alpha (SDF-1a) and the Methacrylate Gelatin (GelMA) microgels which encapsulated insulin-like growth factor-1 (IGF-1) loaded liposomes (Ls) were introduced into Poloxamer 407 (P407) hydrogel matrix. This system achieved the biomimetic release profile of SDF-1a and IGF-1, which covered the early stage from day 1 to 7 and the continuous stage from day 5 to 21, respectively. In vitro study confirmed the enhanced migration, osteogenic biomarker expression, and matrix mineralization of the bone marrow mesenchymal stem cells (BMSCs) co-cultivated with the dual GFs delivering hydrogel/microgels. Transcriptome sequencing revealed that the potential mechanism was associated with mitogen-activated protein kinase (MAPK) signaling activation and its downstream ribosomal protein S6 kinase 2 (RSK2) upregulation. In a critical-sized calvarial defect model in Sprague-Dawley (SD) rats, the injectable hydrogel/microgels system promoted significant bone regeneration. Collectively, our study suggested the current hydrogel/microgels system with the biomimetic release of SDF-1a and IGF-1 efficiently promoted bone regeneration, informing the future development of GF delivery systems intended for bone regeneration therapies.
Topics: Animals; Bone Regeneration; Insulin-Like Growth Factor I; Chemokine CXCL12; Gelatin; Hydrogels; Poloxamer; Rats; Mesenchymal Stem Cells; Rats, Sprague-Dawley; Methacrylates; Osteogenesis; Biomimetic Materials; Drug Liberation; Injections; Male
PubMed: 38821297
DOI: 10.1016/j.ijbiomac.2024.132742 -
Cancer Cell Jun 2024Tumor metastasis requires systemic remodeling of distant organ microenvironments that impacts immune cell phenotypes, population structure, and intercellular...
Tumor metastasis requires systemic remodeling of distant organ microenvironments that impacts immune cell phenotypes, population structure, and intercellular communication. However, our understanding of immune phenotypic dynamics in the metastatic niche remains incomplete. Here, we longitudinally assayed lung immune transcriptional profiles in the polyomavirus middle T antigen (PyMT) and 4T1 metastatic breast cancer models from primary tumorigenesis, through pre-metastatic niche formation, to the final stages of metastatic outgrowth at single-cell resolution. Computational analyses of these data revealed a TLR-NFκB inflammatory program enacted by both peripherally derived and tissue-resident myeloid cells that correlated with pre-metastatic niche formation and mirrored CD14 "activated" myeloid cells in the primary tumor. Moreover, we observed that primary tumor and metastatic niche natural killer (NK) cells are differentially regulated in mice and human patient samples, with the metastatic niche featuring elevated cytotoxic NK cell proportions. Finally, we identified cell-type-specific dynamic regulation of IGF1 and CCL6 signaling during metastatic progression that represents anti-metastatic immunotherapy candidate pathways.
Topics: Animals; Female; Humans; Mice; Lung Neoplasms; Breast Neoplasms; Killer Cells, Natural; Tumor Microenvironment; Disease Progression; Cell Line, Tumor; Lung; Mice, Inbred BALB C; Neoplasm Metastasis; Insulin-Like Growth Factor I; Gene Expression Regulation, Neoplastic; Myeloid Cells; Chemokines, CC; Signal Transduction
PubMed: 38821060
DOI: 10.1016/j.ccell.2024.05.004 -
Turkish Journal of Medical Sciences 2024Atopic dermatitis (AD) is an inflammatory, pruritic, noncontagious, chronic relapsing skin disease. Skin barrier abnormalities, excessive T helper 2 activity, and immune...
BACKGROUND/AIM
Atopic dermatitis (AD) is an inflammatory, pruritic, noncontagious, chronic relapsing skin disease. Skin barrier abnormalities, excessive T helper 2 activity, and immune dysregulation are held responsible. Androgens have a negative effect on the integrity of the epidermal skin barrier, while estrogen has a positive effect. We aimed to investigate whether hormones make a difference between healthy children and children with AD during minipuberty.
MATERIALS AND METHODS
A total of 96 infants (postnatal 4-13 weeks), 48 diagnosed with AD and 48 controls, were included. Each group consisted of 23 girls (47.9%) and 25 boys (52.1%). Anthropometric examinations and hormone measurements were compared.
RESULTS
The two groups, having similar age, sex, body mass index, and weight-for-length standard deviation scores, were compared. Serum free thyroxine (FT4) levels were found to be lower and insulin-like growth factor binding protein-3 (IGFBP3) levels were found to be higher in children with AD (p < 0.001 and p = 0.038, respectively). In girls with AD, estradiol, FT4, and insulin-like growth factor-1 (IGF-1) levels were found to be lower, but thyroid-stimulating hormone (TSH) levels were found to be higher (p = 0.023, p < 0.001, p = 0.038, and p = 0.034, respectively). In boys with AD, the FT4 level was found to be lower (p = 0.023). Serum FT4 and TSH levels were within normal reference ranges in all comparisons.
CONCLUSION
Especially in girls with AD, decreased estradiol and IGF-1 levels were observed compared to the controls during minipuberty. In the logistic regression model, decreased levels of serum estradiol, dehydroepiandrosterone sulfate, FT4, and IGF-1, and increased levels of IGFBP3 were associated with an increased likelihood of exhibiting atopic dermatitis.
Topics: Humans; Dermatitis, Atopic; Female; Male; Insulin-Like Growth Factor Binding Protein 3; Infant; Insulin-Like Growth Factor I; Case-Control Studies; Estradiol; Thyroxine; Puberty; Thyrotropin
PubMed: 38812645
DOI: 10.55730/1300-0144.5795