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Molecular Therapy : the Journal of the... Aug 2023The cornea serves as an important barrier structure to the eyeball and is vulnerable to injuries, which may lead to scarring and blindness if not treated promptly. To...
The cornea serves as an important barrier structure to the eyeball and is vulnerable to injuries, which may lead to scarring and blindness if not treated promptly. To explore an effective treatment that could achieve multi-dimensional repair of the injured cornea, the study herein innovatively combined modified mRNA (modRNA) technologies with adipose-derived mesenchymal stem cells (ADSCs) therapy, and applied IGF-1 modRNA (modIGF1)-engineered ADSCs (ADSC) to alkali-burned corneas in mice. The therapeutic results showed that ADSC treatment could achieve the most extensive recovery of corneal morphology and function when compared not only with simple ADSCs but also IGF-1 protein eyedrops, which was reflected by the healing of corneal epithelium and limbus, the inhibition of corneal stromal fibrosis, angiogenesis and lymphangiogenesis, and also the repair of corneal nerves. In vitro experiments further proved that ADSC could more significantly promote the activity of trigeminal ganglion cells and maintain the stemness of limbal stem cells than simple ADSCs, which were also essential for reconstructing corneal homeostasis. Through a combinatorial treatment regimen of cell-based therapy with mRNA technology, this study highlighted comprehensive repair in the damaged cornea and showed the outstanding application prospect in the treatment of corneal injury.
Topics: Mice; Animals; Insulin-Like Growth Factor I; Adipose Tissue; Cornea; Corneal Injuries; Mesenchymal Stem Cells; Corneal Diseases; Wound Healing
PubMed: 37165618
DOI: 10.1016/j.ymthe.2023.05.002 -
Endocrine Journal Nov 2023Long-term stimulation of thyroid follicular epithelium by high growth hormone (GH) and insulin-like growth factor-1 (IGF-1) in patients with acromegaly can lead to...
Long-term stimulation of thyroid follicular epithelium by high growth hormone (GH) and insulin-like growth factor-1 (IGF-1) in patients with acromegaly can lead to thyroid dysfunction, goiter, thyroid nodules, and even thyroid cancer and thyroid-associated ophthalmopathy (TAO). Excessive GH/IGF-1 promotes goiter and thyroid nodule formation, which can be reversed by normalizing the IGF-1 levels with surgery or medical treatment. Whether patients with acromegaly have an increased risk of thyroid cancer remains controversial, and routine thyroid ultrasonography and regular cancer screening are recommended in such cases, especially when the nodules possess malignant propensity. TAO is an autoimmune disease and newer treatments are being discovered against it. Recent studies have reported that the IGF-1 receptor (IGF-1R) plays an important role in the pathogenesis of TAO, and the IGF-1R inhibitor teprotumumab involves significantly improved disease endpoints in patients with active TAO. Thyroid-stimulating hormone (TSH) receptor (TSHR) and IGF-1R co-immunoprecipitate in orbital and thyroid tissues to form a functional complex; thus, combined therapy targeting TSHR and IGF-1R may be more effective than single therapy.
Topics: Humans; Insulin-Like Growth Factor I; Acromegaly; Receptor, IGF Type 1; Thyroid Diseases; Graves Ophthalmopathy; Goiter; Receptors, Thyrotropin; Human Growth Hormone; Growth Hormone; Thyroid Neoplasms
PubMed: 37880078
DOI: 10.1507/endocrj.EJ23-0356 -
Cell Reports Aug 2023Inadequate remnant volume and regenerative ability of the liver pose life-threatening risks to patients after partial liver transplantation (PLT) or partial hepatectomy...
Inadequate remnant volume and regenerative ability of the liver pose life-threatening risks to patients after partial liver transplantation (PLT) or partial hepatectomy (PHx), while few clinical treatments focus on safely accelerating regeneration. Recently, we discovered that supplementing 5-aminolevulinate (5-ALA) improves liver cold adaptation and functional recovery, leading us to uncover a correlation between 5-ALA metabolic activities and post-PLT recovery. In a mouse 2/3 PHx model, 5-ALA supplements enhanced liver regeneration, promoting infiltration and polarization of anti-inflammatory macrophages via P53 signaling. Intriguingly, chemokine receptor CX3CR1 functions to counterbalance these effects. Genetic ablation or pharmacological inhibition of CX3CR1 (AZD8797; phase II trial candidate) augmented the macrophagic production of insulin-like growth factor 1 (IGF-1) and subsequent hepatocyte growth factor (HGF) production by hepatic stellate cells. Thus, short-term treatments with both 5-ALA and AZD8797 demonstrated pro-regeneration outcomes superior to 5-ALA-only treatments in mice after PHx. Overall, our findings may inspire safe and effective strategies to better treat PLT and PHx patients.
Topics: Animals; Mice; Aminolevulinic Acid; Cell Proliferation; Disease Models, Animal; Hepatocytes; Insulin-Like Growth Factor I; Liver; Liver Regeneration
PubMed: 37578861
DOI: 10.1016/j.celrep.2023.112984 -
Immunology Oct 2023Dachshund family transcription factor 1 (DACH1) has been shown to exhibit a tumour-suppressive role in a number of human cancers. However, the role of DACH1 in...
Dachshund family transcription factor 1 (DACH1) has been shown to exhibit a tumour-suppressive role in a number of human cancers. However, the role of DACH1 in hypopharyngeal squamous cell carcinoma (HPSCC) and its function in the tumour microenvironment (TME) are still not clear. Crosstalk between cancer cells and tumour-associated macrophages (TAMs) mediates tumour progression in HPSCC. The expression of DACH1, CD86 and CD163 was detected in 71 matched HPSCC-non-cancerous tissue pairs using quantitative real-time polymerase chain reaction and IHC analysis. Cell proliferation, migration and invasion were monitored by colony formation, Transwell and EdU incorporation assays. ChIP-qPCR and dual-luciferase reporter assays were applied to verify the targeting relationships between DACH1 and IGF-1. Stably transfected HPSCC cells were co-cultured with MΦ macrophages to assess macrophage polarization and secretory signals. DACH1 was decreased in HPSCC tissues and was indicative of a poor prognosis for HPSCC patients. Decreased DACH1 expression in HPSCC was associated with fewer CD86+ TAMs and more CD163+ TAMs. Knockdown of DACH1 inhibited the proliferation, migration and invasion of FaDu cells via Akt/NF-κB/MMP2/9 signalling. Additionally, DACH1 was found to directly bind to the promoter region of IGF-1 to downregulate the secretion of IGF-1, which inhibited TAMs polarization through the IGF-1R/JAK1/STAT3 axis. Furthermore, in nude mice, the effects of DACH1 inhibition on tumour progression and M2-like TAMs polarization were confirmed. These findings suggest that IGF-1 is a critical downstream effector of DACH1 that suppresses cell migration and invasion and inhibits TAMs polarization. DACH1 could be a therapeutic target and prognostic marker for HPSCC.
Topics: Animals; Humans; Mice; Cell Line, Tumor; Cell Proliferation; Eye Proteins; Head and Neck Neoplasms; Insulin-Like Growth Factor I; Macrophage Activation; Mice, Nude; Squamous Cell Carcinoma of Head and Neck; Transcription Factors; Tumor Microenvironment
PubMed: 37243970
DOI: 10.1111/imm.13667 -
Metabolism: Clinical and Experimental Nov 2023The role of metabolic/inflammatory hormonal systems in metabolic dysfunction associated steatotic liver disease (MASLD) remains to be fully elucidated. (Observational Study)
Observational Study
BACKGROUND
The role of metabolic/inflammatory hormonal systems in metabolic dysfunction associated steatotic liver disease (MASLD) remains to be fully elucidated.
PURPOSE
To report the levels of the novel total and H-specific growth differentiation factor-15 (GDF-15) and other established hormonal systems and to describe hormonal patterns in controls and patients with MASLD and its stages.
METHODS
This is a multicenter study from two Gastroenterology-Hepatology Departments (Greece and Australia) and one Bariatric-Metabolic Surgery Department (Italy). Overall, n = 455 serum samples of patients with biopsy-proven MASLD (n = 374) and Controls (n = 81) were recruited.
RESULTS
We report for the first time that total and H-specific GDF-15 levels are higher in MASLD, at-risk metabolic dysfunction associated steatohepatitis (MASH), and severe fibrosis than in Controls. In addition, follistatin-like-3 (FSTL-3), free insulin-like growth factor-1 (IGF-1), leptin, and insulin levels were higher in MASLD patients than in Controls, while adiponectin levels were lower in MASLD subjects than in Controls. Activin-A, follistatin (FST), FSTL-3, and insulin levels significantly increased in severe fibrosis compared to no/mild fibrosis, while free IGF-1 decreased. In addition, adiponectin levels were lower in subjects without fibrosis vs. any fibrosis. Moreover, GDF-15 presented a strong positive association for the likelihood of having MASLD and at-risk MASH, while in adjusted analyses, FST and adiponectin showed inverse associations. Two different patterns of at-risk MASH were revealed through unsupervised analysis (total variation explained=54%). The most frequent pattern met in our sample (34.3%) was characterized by higher levels of total and H-specific GDF-15, follistatins, and activins, as well as low adiponectin levels. The second pattern revealed was characterized by high levels of free IGF-1, insulin, and leptin, with low levels of activin-A and adiponectin. Similar patterns were also generated in the case of overall MASLD.
CONCLUSIONS
Total and H-specific GDF-15 levels increase as MASLD severity progresses. FSTL-3, free IGF-1, leptin, and insulin are also higher, whereas adiponectin and activin-A levels are lower in the MASLD group than in Controls. Hormonal systems, including GDF-15, may not only be involved in the pathophysiology but could also prove useful for the diagnostic workup of MASLD and its stages and may potentially be of therapeutic value.
Topics: Humans; Leptin; Insulin-Like Growth Factor I; Non-alcoholic Fatty Liver Disease; Follistatin; Growth Differentiation Factor 15; Adiponectin; Insulin; Activins; Fibrosis; Biopsy
PubMed: 37757973
DOI: 10.1016/j.metabol.2023.155694 -
International Journal of Molecular... Oct 2023The Insulin-like growth factor 2 (IGF-2) has been recently proven to alleviate depressive-like behaviors in both rats and mice models. However, its potential role as a...
The Insulin-like growth factor 2 (IGF-2) has been recently proven to alleviate depressive-like behaviors in both rats and mice models. However, its potential role as a peripheral biomarker has not been evaluated in depression. To do this, we measured plasma IGF-2 and other members of the IGF family such as Binding Proteins (IGFBP-1, IGFBP-3, IGFBP-5 and IGFBP-7) in a depressed group of patients (n = 51) and in a healthy control group (n = 48). In some of these patients (n = 15), we measured these proteins after a period (19 ± 6 days) of treatment with antidepressants. The Hamilton Depressive Rating Scale (HDRS) and the Self-Assessment Anhedonia Scale (SAAS) were used to measure depression severity and anhedonia, respectively. The general cognition state was assessed by the Mini-Mental State Examination (MMSE) test and memory with the Free and Cued Selective Reminding Test (FCSRT). The levels of both IGF-2 and IGFBP-7 were found to be significantly increased in the depressed group; however, only IGF-2 remained significantly elevated after correction by age and sex. On the other hand, the levels of IGF-2, IGFBP-3 and IGFBP-5 were significantly decreased after treatment, whereas only IGFBP-7 was significantly increased. Therefore, peripheral changes in the IGF family and their response to antidepressants might represent alterations at the brain level in depression.
Topics: Humans; Rats; Animals; Mice; Insulin-Like Growth Factor II; Insulin-Like Growth Factor Binding Protein 3; Insulin-Like Growth Factor Binding Protein 5; Depressive Disorder, Major; Insulin-Like Growth Factor I; Anhedonia; Antidepressive Agents; Insulin-Like Growth Factor Binding Protein 2
PubMed: 37894932
DOI: 10.3390/ijms242015254 -
Current Osteoporosis Reports Apr 2024To describe the contributions of osteocytes to the lesions in Paget's disease, which are characterized by locally overactive bone resorption and formation. (Review)
Review
PURPOSE OF REVIEW
To describe the contributions of osteocytes to the lesions in Paget's disease, which are characterized by locally overactive bone resorption and formation.
RECENT FINDINGS
Osteocytes, the most abundant cells in bone, are altered in Paget's disease lesions, displaying increased size, decreased canalicular length, incomplete differentiation, and less sclerostin expression compared to controls in both patients and mouse models. Pagetic lesions show increased senescent osteocytes that express RANK ligand, which drives osteoclastic bone resorption. Abnormal osteoclasts in Paget's disease secrete abundant IGF1, which enhances osteocyte senescence, contributing to lesion formation. Recent data suggest that osteocytes contribute to lesion formation in Paget's disease by responding to high local IGF1 released from abnormal osteoclasts. Here we describe the characteristics of osteocytes in Paget's disease and their role in bone lesion formation based on recent results with mouse models and supported by patient data.
Topics: Osteitis Deformans; Osteocytes; Humans; Animals; Osteoclasts; RANK Ligand; Bone Resorption; Mice; Insulin-Like Growth Factor I; Disease Models, Animal; Cellular Senescence
PubMed: 38457001
DOI: 10.1007/s11914-024-00863-5 -
Cells Dec 2023The high prevalence of sarcopenia in an aging population has an underestimated impact on quality of life by increasing the risk of falls and subsequent hospitalization.... (Review)
Review
The high prevalence of sarcopenia in an aging population has an underestimated impact on quality of life by increasing the risk of falls and subsequent hospitalization. Unfortunately, the application of the major established key therapeutic-physical activity-is challenging in the immobile and injured sarcopenic patient. Consequently, novel therapeutic directions are needed. The transcription factor Forkhead-Box-Protein O3 (FOXO3) may be an option, as it and its targets have been observed to be more highly expressed in sarcopenic muscle. In such catabolic situations, induces the expression of two muscle specific ubiquitin ligases ( and ) via the PI3K/AKT pathway. In this review, we particularly evaluate the potential of -targeted gene therapy. knockdown has been shown to lead to increased muscle cross sectional area, through both the AKT-dependent and -independent pathways and the reduced impact on the two major downstream targets and . Moreover, a reduction suppresses apoptosis, activates satellite cells, and initiates their differentiation into muscle cells. While this indicates a critical role in muscle regeneration, this mechanism might exhaust the stem cell pool, limiting its clinical applicability. As systemic knockdown has also been associated with risks of inflammation and cancer progression, a muscle-specific approach would be necessary. In this review, we summarize the current knowledge on and conceptualize a specific and targeted therapy that may circumvent the drawbacks of systemic knockdown. This approach presumably would limit the side effects and enable an activity-independent positive impact on skeletal muscle.
Topics: Humans; Aged; Sarcopenia; Proto-Oncogene Proteins c-akt; Phosphatidylinositol 3-Kinases; Forkhead Transcription Factors; Insulin-Like Growth Factor I; Quality of Life; Signal Transduction; Forkhead Box Protein O3
PubMed: 38132107
DOI: 10.3390/cells12242787 -
Endocrine-related Cancer Sep 2023Despite landmark advances in cancer treatments over the last 20 years, cancer remains the second highest cause of death worldwide, much ascribed to intrinsic and... (Review)
Review
Despite landmark advances in cancer treatments over the last 20 years, cancer remains the second highest cause of death worldwide, much ascribed to intrinsic and acquired resistance to the available therapeutic options. In this review, we address this impending issue, by focusing the spotlight on the rapidly emerging role of growth hormone action mediated by two intimately related tumoral growth factors - growth hormone (GH) and insulin-like growth factor 1 (IGF1). Here, we not only catalog the scientific evidences relating specifically to cancer therapy resistance inflicted by GH and IGF1 but also discuss the pitfalls, merits, outstanding questions and the future need of exploiting GH-IGF1 inhibition to tackle cancer treatment successfully.
Topics: Humans; Human Growth Hormone; Insulin-Like Growth Factor I; Neoplasms; Growth Hormone
PubMed: 37283510
DOI: 10.1530/ERC-22-0414 -
Alzheimer's Research & Therapy Aug 2023The effects of insulin-like growth factor-1 (IGF-1) deficiency on cognitive decline have been consistently reported in animal studies, but the relationship between IGF-1...
BACKGROUND
The effects of insulin-like growth factor-1 (IGF-1) deficiency on cognitive decline have been consistently reported in animal studies, but the relationship between IGF-1 and human brain health remains controversial. Our study aimed to investigate the associations of serum IGF-1 concentrations with some brain-related disorders and neuroimaging features.
METHODS
This prospective study included 369,711 participants (55.8 ± 8.1 years) from the UK biobank who had serum IGF-1 measured and were free from brain-related disorders of interest - dementia, stroke, and Parkinson's disease (PD) - at enrollment (2006-2010). Restricted cubic splines and Cox proportional hazards models were used to detect the associations between IGF-1 concentrations and brain-related diseases. In addition, general linear regressions were applied to explore the relationship between IGF-1 concentrations and neuroimaging features (volumes of white matter, grey matter, and hippocampus and white matter hyperintensity) among a sub-sample of 36,458 participants with magnetic resonance imaging data collected since 2014.
RESULTS
During a median follow-up of 12.6 years, a total of 4,857 dementia, 6,240 stroke, and 2,116 PD cases were documented. The dose-response analyses yielded U-shaped relationships between IGF-1 concentrations and risks of dementia and stroke (P < 0.001 for non-linearity), with the lowest risks at 18 nmol/L and 26 nmol/L, respectively. A positive linear relationship was observed between IGF-1 concentrations and risk of PD (P = 0.163 for non-linearity). Moreover, neuroimaging analyses showed that higher IGF-1 concentrations were associated with greater volumes of white matter (β = 2.98 × 10, P < 0.001) and hippocampus (β = 3.37 × 10, P = 0.002) and smaller white matter hyperintensity (β = -3.12 × 10, P < 0.001).
CONCLUSIONS
Apart from the diverse associations with neuroimaging features, both low and high IGF-1 concentrations are associated with increased risks of dementia and stroke and higher IGF-1 concentrations are linked to a higher risk of PD, highlighting the potential of IGF-1 as a biomarker for risk stratification of brain health.
Topics: Humans; Biological Specimen Banks; Brain; Dementia; Insulin-Like Growth Factor I; Prospective Studies; Stroke; United Kingdom
PubMed: 37608387
DOI: 10.1186/s13195-023-01288-5