Insulin-like Growth Factor Pathway Research Articles

Single-nucleus transcriptomics of epicardial adipose tissue from female pigs reveals effects of exercise training on resident innate and adaptive immune cells

BackgroundCoronary artery disease (CAD) is a leading cause of death in women. Epicardial adipose tissue (EAT) secretes cytokines to modulate coronary artery function, and the release of fatty acids from EAT serves as a readily available energy source for cardiomyocytes. However, despite having beneficial functions, excessive amounts of EAT can cause the secretion of proinflammatory molecules that increase the instability of atherosclerotic plaques and contribute to CAD progression. Although exercise mitigates CAD, the mechanisms by which exercise impacts EAT are unknown. The Yucatan pig is an excellent translational model for the effects of exercise on cardiac function. Therefore, we sought to determine if chronic aerobic exercise promotes an anti-inflammatory microenvironment in EAT from female Yucatan pigs.MethodsSexually mature, female Yucatan pigs (n = 7 total) were assigned to sedentary (Sed, n = 3) or exercise (Ex, n = 4) treatments, and coronary arteries were occluded (O) with an ameroid to mimic CAD or remained non-occluded (N). EAT was collected for bulk (n = 7 total) and single nucleus transcriptomic sequencing (n = 2 total, 1 per exercise treatment).ResultsBased on the bulk transcriptomic analysis, exercise upregulated S100 family, G-protein coupled receptor, and CREB signaling in neurons canonical pathways in EAT. The top networks in EAT affected by exercise as measured by bulk RNA sequencing were SRC kinase family, fibroblast growth factor receptor, Jak-Stat, and vascular endothelial growth factor. Single nucleus transcriptomic analysis revealed that exercise increased the interaction between immune, endothelial, and mesenchymal cells in the insulin-like growth factor pathway and between endothelial and other cell types in the platelet endothelial cell adhesion molecule 1 pathway. Sub-clustering revealed nine cell types in EAT, with fibroblast and macrophage populations predominant in O-Ex EAT and T cell populations predominant in N-Ex EAT. Unlike the findings for exercise alone as a treatment, there were not increased interactions between endothelial and mesenchymal cells in O-Ex EAT. Coronary artery occlusion impacted the most genes in T cells and endothelial cells. Genes related to fatty acid metabolism were the most highly upregulated in non-immune cells from O-Ex EAT. Sub-clustering of endothelial cells revealed that N-Ex EAT separated from other treatments.ConclusionsAccording to bulk transcriptomics, exercise upregulated pathways and networks related to growth factors and immune cell communication. Based on single nucleus transcriptomics, aerobic exercise increased cell-to-cell interaction amongst immune, mesenchymal, and endothelial cells in female EAT. Yet, exercise was minimally effective at reversing alterations in gene expression in endothelial and mesenchymal cells in EAT surrounding occluded arteries. These findings lay the foundation for future work focused on the impact of exercise on cell types in EAT.

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.

Dysfunction in IGF2R Pathway and Associated Perturbations in Autophagy and WNT Processes in Beckwith-Wiedemann Syndrome Cell Lines.

Beckwith-Wiedemann Syndrome (BWS) is an imprinting disorder characterized by overgrowth, stemming from various genetic and epigenetic changes. This study delves into the role of IGF2 upregulation in BWS, focusing on insulin-like growth factor pathways, which are poorly known in this syndrome. We examined the IGF2R, the primary receptor of IGF2, WNT, and autophagy/lysosomal pathways in BWS patient-derived lymphoblastoid cell lines, showing different genetic and epigenetic defects. The findings reveal a decreased expression and mislocalization of IGF2R protein, suggesting receptor dysfunction. Additionally, our results point to a dysregulation in the AKT/GSK-3/mTOR pathway, along with imbalances in autophagy and the WNT pathway. In conclusion, BWS cells, regardless of the genetic/epigenetic profiles, are characterized by alteration of the IGF2R pathway that is associated with the perturbation of the autophagy and lysosome processes. These alterations seem to be a key point of the molecular pathogenesis of BWS and potentially contribute to BWS's characteristic overgrowth and cancer susceptibility. Our study also uncovers alterations in the WNT pathway across all BWS cell lines, consistent with its role in growth regulation and cancer development.

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.

Associations Between Hypertension, Angiotensin-Converting Enzyme Inhibitors, and Physical Performance in Very Old Adults: Results from the ilSIRENTE Study

BackgroundResults regarding the associations between hypertension-related parameters and physical performance in older adults are conflicting. A possible explanation for these divergent results is that investigations may not have adjusted their analyses according to the use of angiotensin-converting enzyme inhibitors (ACEIs).ObjectivesTo examine the associations between hypertension-related parameters, ACEI use, and a set of physical performance tests in very old adults.DesignCross-sectional study from the ilSIRENTE database.SettingMountain community of the Sirente geographic area (L’Aquila, Abruzzo, Italy).ParticipantsAll persons born in the Sirente area (13 municipalities) before 1 January 1924 and living in that region at the time of study were identified and invited to participate. The final sample included 364 older adults (mean age: 85.8 ± standard deviation [SD] 4.8).MeasurementsPhysical performance was assessed using isometric handgrip strength (IHG), walking speed (WS) at normal and fast pace, 5-time sit-to-stand test (5STS), and muscle power measures. Blood pressure (BP) was measured after 20 to 40 min of rest, while participants sat in an upright position. Drugs were coded according to the Anatomical Therapeutic and Chemical codes. ACEIs were categorized in centrally (ACEI-c) and peripherally (ACEI-p) acting. Blood inflammatory markers, free insulin-like growth factor 1 (IGF-1), and IGF-binding protein 3 (IGFBP-3) were assayed.ResultsResults indicated that 5STS test was significantly and negatively associated with diastolic BP values. However, significance was lost when results were adjusted for ACEI use. Participants on ACEIs were more likely to have greater specific muscle power and higher blood levels of IGFBP-3 than non-ACEI users. When participants were categorized according to ACEI subtypes, those on ACEI-p had higher blood IGF-1 levels compared with ACEI-c users.ConclusionsThe main findings of the present study indicate that ACEI use might influence the association between hypertension-related parameters and neuromuscular parameters in very old adults. Such results may possibly be linked to the effects of ACEI-p on the IGF-1 pathway.

Oral administration of ellagic acid mitigates perioperative neurocognitive disorders, hippocampal oxidative stress, and neuroinflammation in aged mice by restoring IGF-1 signaling

This study investigates the potential of ellagic acid (EA), a phytochemical with antioxidant and anti-inflammatory properties, in managing perioperative neurocognitive disorders (PND). PND, which represents a spectrum of cognitive impairments often faced by elderly patients, is principally linked to surgical and anesthesia procedures, and heavily impacted by oxidative stress in the hippocampus and microglia-induced neuroinflammation. Employing an aged mice model subjected to abdominal surgery, we delve into EA's ability to counteract postoperative oxidative stress and cerebral inflammation by engaging the Insulin-like growth factor-1 (IGF-1) pathway. Our findings revealed that administering EA orally notably alleviated post-surgical cognitive decline in older mice, a fact that was manifested in improved performance during maze tests. This enhancement in the behavioral performance of the EA-treated mice corresponded with the rejuvenation of IGF-1 signaling, a decrease in oxidative stress markers in the hippocampus (like MDA and carbonylated protein), and an increase in the activity of antioxidant enzymes such as SOD and CAT. Alongside these, we observed a decrease in microglia-driven neuroinflammation in the hippocampus, thus underscoring the antioxidant and anti-inflammatory roles of EA. Interestingly, when EA was given in conjunction with an IGF1R inhibitor, these benefits were annulled, accentuating the pivotal role that the IGF-1 pathway plays in the neuroprotective potential of EA. Hence, EA could serve as a potent candidate for safeguarding against PND in older patients by curbing oxidative stress and neuroinflammation through the activation of the IGF-1 pathway.

Hemoglobin Response to Zinc Supplementation in Patients with Zinc Deficiency and Chronic Anemia

Background: Zinc is a necessary micronutrient used as a catalyst, structural element, and regulatory ion in many metabolic processes including erythropoiesis. Chronic anemia has an estimated prevalence of 5.6% within the US according to NHANES. Iron deficiency is considered the most common nutritional deficiency leading to anemia, but other nutritional deficiencies have been implicated in anemia including deficiencies of Vitamin A, B12, B6, C, D, and E, folate, Riboflavin, Copper, and Zinc. While zinc fortification has been studied in developing countries and has been associated with a decrease in the overall prevalence of anemia within the pediatric and maternal populations, there have been no studies in adults with chronic anemic in the developed world. The mechanism of Zinc in erythropoiesis is likely multifactorial with zinc acting as a catalyst in alpha-aminolevulinic acid dehydratase enzyme in iron metabolism and heme synthesis. Zinc's incorporation in the structure of the growth factor independent 1B (Gfi-1B) Zinc finger protein and GATA-1 Zinc finger transcription factor, which functions as a regulator in erythroid cell growth by modulating gene expression specific to erythroid series including the SMAD pathways and TGF-β signaling. Zinc's interaction in signaling cascades such as the growth hormone and insulin-like growth factor-1 pathways also result in increased erythropoietin transcription and therefore increased erythropoiesis. In addition, zinc is regarded as an important erythroid differentiation factor. This descriptive, retrospective study describes zinc deficient patients with chronic anemia, who underwent zinc supplementation, and their changes in hemoglobin (HGB) over a 12-month period in an academic outpatient hematology center in California, United States of America. Objectives: Primary endpoints: determine the rate of anemia resolution over 12 months following supplementation of zinc in patients with zinc deficiency and chronic anemia. Secondary endpoints: determine if zinc supplementation in zinc deficient patients with chronic anemia will improve HGB by at least 1.0 g.dL by 1, 3, 6, and 12 month time points. Methods: Ninety Three patients with chronic anemia (HGB <12 for women, HGB <13 for men for >3 months) over the age of 18 were identified to have zinc deficiency (plasma zinc concentration <65 ug/dL) in an academic outpatient hematology center in California. Patients did not start new treatment for their anemia, including initiating new treatments for malignancy 3 months preceding, and within the data collection period. Patients were supplemented with Zinc Sulfate 50 mg daily and their HGB was followed over 12 months. A retrospective analysis was completed for prior medical history, lab data, and HGB was tabulated at the time markers of 1, 3, 6, and 12 months following initiation of zinc supplementation. ANOVA, Wilcoxon rank-sum, and unpaired Students and t tests were performed to determine significant differences where p <0.05 is considered statistically significant. Results Prior to supplementation, average HGB among patients was 9.83 g/dL, WBC was 6.8 g/dL, MCV was 89 fl, PLTS were 211 g/dL. Following 1 month of supplementation average HGB was 10.46 g/dL (p = 0.015, n = 82), at 3 months average HGB was 10.75 g/dL (p = 0.0002, n = 83), at 6 months average HGB was 11.34 g/dL (p= 0.000000004, n = 74), and at 12 months average HGB was 11.48 g/dL (p = 0.00000002, n= 57). Primary endpoint of anemia resolution was found in 39 of 93 patients (42%). Secondary endpoint of HGB improvement by at least 1.0 g/dL was reached in 31% of patients at 1 month, 36% of patients at 3 months, 58% of patients at 6 months and 68% of patients at 12 months. Conclusions: Zinc supplementation significantly improved HGB levels in patients with zinc deficiency and chronic anemia, with resolution of anemia in 42% of patients. There was statistically significant improvement from baseline HGB at the1, 3, 6, and 12 month time markers. Further study is warranted to determine the specific mechanism of zinc deficiency in anemia, as well as clinical studies determining zinc supplementation doses, monitoring, and toxicity.

Hemoglobin Response to Zinc Supplementation in Chronic Kidney Disease in Patients with Zinc Deficiency and Anemia

Background: Chronic anemia has an estimated prevalence of 5.6% within the US, where 25.3% of patients with chronic kidney disease (CKD) 3-5 have anemia of chronic kidney disease according to NHANES. Anemia in CKD has long been attributed to a decrease in EPO production due to their kidney disease. While iron deficiency is treated in anemia of chronic kidney disease, other micronutrients are less commonly tested or supplemented. Zinc may be an additional micronutrient of interest in anemia of chronic kidney disease as zinc has numerous proposed mechanisms in erythropoeisis including acting as a catalyst in the iron metabolism and heme synthesis through the activity of alpha-aminolevulinic acid dehydratase enzyme. Zinc is found in the structure of the growth factor independent 1B (Gfi-1B) Zinc finger protein and GATA-1 Zinz finger transcription factor, which functions as a regulator in erythroid cell growth by modulating gene expression specific to erythroid series including the SMAD pathways and TGF-β signaling. The interaction with zinc in signaling cascades such as the growth hormone and insulin-like growth factor-1 pathways also result in increased erythropoietin transcription and therefore increased erythropoiesis. In addition, zinc is regarded as an important erythroid differentiation factor which progress maturation of erythrocytes. Zinc has also shown to stimulate EPO production in nephrectomized rats and Zinc supplementation increased reticulocyte production in human subjects. This descriptive, retrospective study describes zinc deficient patients with CKD 3-5 and chronic anemia; who underwent oral zinc supplementation, and their changes in hemoglobin (HGB) over a 12 month period in an academic outpatient hematology clinic in California, United States of America. Objectives: Primary endpoints: determine the rate of anemia resolution over 12 months following supplementation of zinc in patients with zinc deficiency, CKD, and anemia of chronic kidney disease. Secondary endpoints: determine if zinc supplementation in zinc deficient patients with chronic anemia and CKD 3-5 will improve HGB by at least 1.0 g.dL by 1, 3, 6, and 12 month time points. Methods: Hematology patients from Loma Linda University Cancer Center over the age of 18 who had CKD 3 or above (GFR <59 ml/min) with chronic anemia (HGB <12 for women, HGB <13 for men for >3 months) were identified to have zinc deficiency (plasma zinc concentration <65 ug/dL). Patients did not start new treatment for their anemia, including initiating new treatments for malignancy 3 months preceding, and within the data collection period. Patients were supplemented with Zinc Sulfate 50 mg daily and their HGB was followed over 12 months. A retrospective analysis was completed for prior medical history, lab data, and hemoglobin was tabulated at the time markers of 1, 3, 6, and 12 months following initiation of zinc supplementation. ANOVA, Wilcoxon rank-sum, and unpaired Students and t tests were performed to determine significant differences. p <0.05 is considered statistically significant. Results Thirty-Four patients were identified to have CKD 3-5 with chronic anemia and zinc deficiency. They were found to have no statistically significant baseline characteristics, hematologic values at time of diagnosis, or micronutrient and hormonal etiologies for anemia. HGB prior to supplementation averaged 9.96 g/dL, WBC averaged 5.8, and PLTS averaged 149. Following supplementation HGB at 1 month average was 10.47 g/dL (p=0.19 n=30), at 3 months average of 10.49 (p=0.12 n=31), at 6 months average of 11.03 (p=0.011 n=27), at 1 year 10.93 (p=0.03, n=17). Primary endpoint of HGB resolution was found in 12 of the 34 patients (35%). Secondary endpoint of HGB improvement by at least 1.0 g/dL was reached in 27% of patients at 1 month, 32% of patients at 3 months, 59% of patients at 6 months and 64% of patients at 12 months. Conclusions: Zinc supplementation improved patients' anemia with resolution of anemia in 35% of patients with incremental improvement in HGB over a 1 year time frame. There was statistically significant improvement from baseline HGB at the 6 and 12 month time markers. Further study is warranted to determine the specific mechanism of zinc deficiency in anemia with chronic kidney disease, as well as clinical studies determining zinc supplementation doses, monitoring, and toxicity.

Zinc As an Erythrocyte Stimulating Agent in Myelodysplastic Syndrome

Background: The anemia highly associated with myelodysplastic syndrome (MDS) has been linked to numerous transcriptional factor regulation abnormalities, specifically SMAD 2/3 upregulation that forms an inhibitory feedback loop to downregulate erythrocyte stimulation (ESA), which can have therapeutic implications. There is evidence that zinc contributes to erythropoiesis through multifactorial mechanisms involving regulation and transportation of necessary micronutrients including copper and iron. Zinc is involved in cell signaling pathways for erythropoiesis including acting as a cofactor in the SMAD 2/3 complex, TGF-β signaling, and incorporation of zinc into GATA-1 (Zinc finger transcription factor). The interaction with zinc in signaling cascades such as the growth hormone and insulin-like growth factor-1 pathways also result in increased erythropoietin transcription and therefore increased erythropoiesis. In addition, zinc is regarded as an important erythroid differentiation factor which progress maturation of erythrocytes. Due to the multifactorial role of zinc in erythropoiesis, including acting as a cofactor in the SMAD 2/3 complex, it may represent an inexpensive, and well tolerated ESA or additional micronutrient to test and supplement in MDS. This descriptive, retrospective study describes zinc deficient patients with MDS, who underwent zinc supplementation, and their changes in hemoglobin (HGB) over a 12-month period in an academic outpatient hematology center in California, United States of America. Objectives: Primary endpoints: determine if zinc supplementation in zinc deficient MDS patients will improve HGB by at least 1.0 g.dL by 1, 3, 6, and 12 month time points. Methods: Eight adult patients with MDS were identified to have zinc deficiency (plasma zinc concentration <65 ug/dL). Patients were not started on ESAs or their treatments were not changed for the management of their MDS. Patients were supplemented with Zinc Sulfate 50 mg daily and their HGB was followed over 12 months. A retrospective analysis for medical history and lab data at time of zinc deficiency diagnosis and at 1, 3, 6 and 12 month following initiation of zinc supplementation was completed. ANOVA, Wilcoxon rank-sum, and unpaired Students and t tests were performed to determine significant differences where p <0.05 is considered statistically significant. Results: Prior to supplementation, average HGB among patients was 8.01 g/dL, WBC was 3.65 g/dL, MCV was 97.6 fl, PLTS were 140g/dL. Following 1 month of supplementation average HGB was 8.5 g/dL (p = 0.5, n = 7), at 3 months average HGB was 9.27 g/dL (p = 0.087, n = 7), at 6 months average HGB was 10.3 g/dL (p= 0.006, n = 7), and at 12 months average HGB was 10.28 g/dL (p = 0.04, n= 7). Primary endpoint of HGB improvement by at least 1.0 g/dL was reached in 29% of patients at 1 month, 43% of patients at 3 months, 86% of patients at 6 months and 71% of patients at 12 months. Resolution of anemia was reached in 1 patient (12.5%) of patients within 12 months. Conclusions: Zinc supplementation improved anemia in MDS patients with incremental improvement in HGB over a 1 year time frame. There was statistically significant improvement from baseline HGB at the 3, 6, and 12 month time markers. Further study is warranted to determine the specific mechanism of zinc deficiency in MDS and its mechanism as an erythrocyte stimulating agent as well as further study in non-zinc deficient patients, various zinc supplementation doses, monitoring, and toxicity.

FRI015 Single Nuclei Transcriptomics Of Epicardial Adipose Tissue From Female Pigs Reveals Differential Effects Of Endurance Exercise On Resident Innate And Adaptive Immune Cells

Abstract Disclosure: I. Ahmad: None. P. Faulkner: None. S. Gupta: None. D. Mullens: None. M. Thomas: None. S.P. Sytha: None. I. Ivan: None. J.J. Cai: None. C.L. Heaps: None. A.E. Newell-Fugate: None. Coronary artery disease (CAD) is the leading cause of global mortality. Although exercise training mitigates CAD progression, the mechanisms by which exercise training impacts epicardial adipose tissue (EAT) are unknown. We hypothesized that exercise training modulates EAT to promote an anti-inflammatory microenvironment in the coronary arteries of female pigs. Female Yucatan pigs (n=7) had an occluder placed around the proximal left circumflex artery. Eight-weeks postoperatively, pigs were assigned to sedentary or exercise groups with exercised pigs undergoing a 14-week treadmill running program. Upon termination, EAT was snap frozen. Bulk transcriptome sequencing was performed, and log fold change expression data was analyzed with Ingenuity Pathway Analysis. Microdroplet-based single nuclei transcriptome was analyzed using Seurat pipeline. Cell-cell interactome (CCI) analysis was performed using CellChat. Bulk RNA-sequencing revealed G-protein coupled receptor signaling, S100 family signaling, FAK signaling, and glutathione-mediated detoxification pathways were upregulated with exercise. Cellular movement, cell to cell communication, inflammatory response, and immune cell trafficking were predicted to be upregulated in exercised EAT. In adipocyte, B cell, and endothelial cell clusters, exercise induced upregulation of genes related to fatty acid synthesis and cellular metabolism. Exercise also caused upregulation of cell adhesion associated oncogene regulated and downregulation of S100 calcium binding protein A9 in B cells. By contrast, exercise caused downregulation of genes related to cell-cell adhesion and cellular metabolism in T cells. Although exercise increased macrophage numbers in EAT, macrophages displayed downregulation of genes related to protein folding and trafficking. Smooth muscle cells from exercised EAT showed upregulation of genes related to lipoprotein and glycogen turnover. CCI revealed increased interactions among all cell types in the insulin-like growth factor pathway of exercised EAT. By contrast, EAT from sedentary pigs had increased CCI for platelet derived growth factor (all cell types), galectin and WNT signaling (immune and mesenchymal cells), TGF (adipocytes, immune and mesenchymal cells), and VEGF (adipocytes, immune and endothelial cells). These findings suggest that exercise training downregulates genes related to cellular function in immune cells from both the innate (macrophages) and adaptive immune systems (T cells), but stimulates genes related to cellular metabolism and migration in B cells from EAT. CCI results suggest that sedentary EAT may secrete increased factors to stimulate inflammation, cell movement, and cell growth. These results provide a foundation for future functional studies of the effects of exercise on EAT and coronary artery regulation. Presentation: Friday, June 16, 2023

The Relationship between IGF Pathway and Acquired Resistance to Tyrosine Kinase Inhibitors in Cancer Therapy.

The tyrosine kinase signaling pathway is an important pathway for cell signal transduction, and is involved in regulating cell proliferation, cell cycle, apoptosis and other essential biological functions. Gene mutations involved in the tyrosine kinase signaling pathway often lead to the development of cancers. Epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor-2 (HER2) are well known receptor tyrosine kinases (RTKs), which belong to the ERBB family and have high mutation frequency in cancers. Tyrosine kinase inhibitors (TKI) targeting EGFR and HER2 have been widely used in the clinical treatment of lung and breast cancers. However, after a period of treatment, patients will inevitably develop resistance to TKI. The insulin-like growth factor (IGF) receptor family, like the ERBB receptor family, belongs to the receptor tyrosine kinase superfamily, which also conducts an important cell signal transduction function. There is an overlap between IGF signaling and EGFR signaling in biological functions and downstream signals. In this review, we summarize the current state of knowledge of how IGF signaling interacts with EGFR signaling can influence cell resistance to EGFR/HER2-TKI. We also summarize the current drugs designed for targeting IGF signaling pathways and their research progress, including clinical trials and preclinical studies. Altogether, we aimed to discuss the future therapeutic strategies and application prospects of IGF signaling pathway targeted therapy.

Pan-cancer analysis of oncogenic role of insulin-like growth factor-binding proteins and validation in ovarian cancer.

Numerous studies have shown that the insulin-like growth factor (IGF) pathway is highly associated with tumor initial and progression in several tumors. However, compared with IGF1/1R and IGF2/2R, insufficient studies have focused on IGF-binding proteins (IGFBPs). The GDC TCGA and GTEx data of 33 cancers, TCGA pan-cancer immune phenotypes, tumor mutation burdens, and the copy number alterations of IGFBPs were extracted. Next, the prognostic value of IGFBPs was analyzed based on a univariate Cox analysis. Additionally, the ESTIMATE algorithm was used to calculate stromal and immune scores and tumor purity, and the CIBERSORT algorithm was used to estimate tumor-infiltrating immunocyte levels. Ultimately, the correlation between IGFBP expression and cancer hallmark pathways was estimated with a Spearman analysis. The expression of IGFBPs was differentially expressed and correlated with prognosis in specific cancers. IGFBPs may operate as biological markers for carcinogenesis and progression and as prognostic biomarkers. Additionally, IGFBP5 has been proved that promotes the invasion and migration of ovarian cancer. In general, IGFBPs can serve as predictable biomarkers and potential therapeutic targets for specific tumors. Our results could provide underlying targets for the design of laboratory experiments to elucidate the mechanism of IGFBPs in cancers and identify IGFBP5 as a prognostic factor in ovarian cancers.

Effect of gastrodin against cognitive impairment and neurodegeneration in APP/PS1 mice via regulating gut microbiota-gut-brain axis.

Gastrodin (Gas) has exhibited protective activity in neurological disorders. Here, we investigated the neuroprotective effect and potential mechanisms of Gas against cognitive impairment via regulating gut microbiota. APPswe/PSEN1dE9 transgenic (APP/PS1) mice were treated intragastrically with Gas for 4weeks, and then cognitive deficits, deposits of amyloid-β (Aβ) and phosphorylation of tau were analyzed. The expression levels of insulin-like growth factor-1 (IGF-1) pathway-related proteins, such as cAMP response element-binding protein (CREB), were detected. Meanwhile, gut microbiota composition was evaluated. Our results showed that Gas treatment significantly improved cognitive deficits and Aβ deposition in APP/PS1 mice. Moreover, Gas treatment increased the level of Bcl-2 and decreased level of Bax and ultimately inhibited neuronal apoptosis. Gas treatment markedly increased the expression levels of IGF-1 and CREB in APP/PS1 mice. Moreover, Gas treatment improved abnormal composition and structure of gut microbiota in APP/PS1 mice. These findings revealed that Gas actively participated in regulating the IGF-1 pathway to inhibit neuronal apoptosis via the gut-brain axis and that it can be considered a new therapeutic strategy against Alzheimer's disease.

Associations of CTCF and FOXA1 with androgen and IGF pathways in men with localized prostate cancer

AimsTo examine associations between the transcription factors CCCTC-binding factor (CTCF) and forkhead box protein A1 (FOXA1) and the androgen receptor (AR) and their association with components of the insulin-like growth factor (IGF)-pathway in a cohort of men with localized prostate cancer. MethodsUsing prostate tissue samples collected during the Prostate cancer: Evidence of Exercise and Nutrition Trial (PrEvENT) trial (N = 70 to 92, depending on section availability), we assessed the abundance of CTCF, FOXA1, AR, IGFIR, p-mTOR, PTEN and IGFBP-2 proteins using a modified version of the Allred scoring system. Validation studies were performed using large, publicly available datasets (TCGA) (N = 489). ResultsWe identified a strong correlation between CTCF and AR staining with benign prostate tissue. CTCF also strongly associated with the IGFIR, with PTEN and with phospho-mTOR. FOXA1 was also correlated with staining for the IGF-IR, with IGFBP-2 and with staining for activated phosphor-mTOR. The staining for the IGF-IR was strongly correlated with the AR. ConclusionOur findings emphasise the close and complex links between the endocrine controls, well known to play an important role in prostate cancer, and the transcription factors implicated by the recent genetic evidence.

Transcriptomic analysis provides new insights into the secondary follicle growth in spotted scat (Scatophagus argus)

Spotted scat (Scatophagus argus) is an important mariculture fish that is of great economic significance in East and Southeast Asia. To date, there are no studies on ovary development and regulation in S. argus. Herein, the ovary transcriptome profiles of S. argus at different stages were constructed, and the genes and pathways potentially involved in secondary follicle growth were identified. A total of 25,426 genes were detected by sequencing the mRNAs from the ovary libraries at stage III (n=3) and IV (n=3). Notably, 2950 and 716 genes were up-regulated and down-regulated in the stage IV ovary, respectively, compared to the stage III ovary. The differentially expressed genes (DEGs) were found to be mostly involved in regulating steroidogenesis, vitellogenesis, lipid metabolism, and meiosis. Up-regulation of steroid hormone synthesis pathway genes (fshr, cyp17a1, and foxl2) and insulin-like growth factor pathway genes (igf1r, ifg2r, igfbp1, igfbp3, and igfbp7) in the ovary at stage IV was possibly the reason for the increased serum estrogen. Moreover, ppara, ppard, fabp3, and lpl were up-regulated in the stage IV ovary and were potentially involved in the lipid droplet formation in the oocyte. Many DEGs were involved in the cellular cycle, meiosis, and cAMP or cGMP synthesis and hydrolysis, indicating that meiosis was restarted at stage IV ovary. In addition, numerous TGF-beta signal pathway genes were up-regulated in the stage IV ovary. This ovary transcript dataset forms a baseline for investigating functional genes associated with oogenesis in S. argus.

Role of insulin-like growth factor, pro-inflammatory and anti-inflammatory cytokines, transcription factors and adipokines in development of hepatocellular carcinoma in metabolic syndrome

Conflicting data on the role of the metabolic syndrome (MS) in the development of hepatocellular carcinoma (HCC) require studies on the influence of molecular factors that are important in the development of HCC in MS, which was the goal of our review. Publications (scientific articles and reviews) over the past 10 years were studied and analyzed using the databases Web of Science, Scopus, PubMed, RSCI. The terms used for the search were “metabolic syndrome and non-alcoholic fatty liver disease”, “metabolic syndrome and non-alcoholic steatohepatitis”, “metabolic syndrome and hepatocellular carcinoma”. The total number of publications studied in all databases exceeded 570 units, while the review presents the most significant results at the present stage. Insulin resistance and obesity, through the development of a systemic chronic inflammatory state, lead to increased inflammation and fibrosis in the liver, which are prodromal signs of hepatocarcinogenesis, increase the production of insulin-like growth factor-1 and disrupt the regulation of the insulin-like growth factor pathway. People with HCC have been shown to overexpress IGF-2. IGF-binding proteins, due to the reduced bioavailability of free IGF-1 and IGF-2 in the circulation, are able to inhibit the growth of HCC. In MS, a pro-inflammatory state is detected, which is caused by the production of cytokines by adipocytes (IL-6, IL-8, IL-1β, tumor necrosis factor α (TNFα), VEGF and chemokine ligands 2 and 5), which recruit immune cells, promoting angiogenesis and enhancing chronic inflammation. Transcription factors (PPAR) are involved in hepatocarcinogenesis, the significance of different factors is not fully understood. Leptin has a positive prognostic value in HCC, improving overall survival, and visfatin has a negative effect on hepatocarcinogenesis. Activation of PAI-1 inhibits the progression of HCC through PPARγ stimulation. Adiponectin may be a prognostic marker in HCC, with a lower serum concentration positively correlated with worse prognosis.

Bone loss is ameliorated by fecal microbiota transplantation through SCFA/GPR41/ IGF1 pathway in sickle cell disease mice

Bone loss is common in sickle cell disease (SCD), but the molecular mechanisms is unclear. Serum insulin-like growth factor 1 (IGF1) was low in SCD subjects and SCD mice. To determine if decreased IGF1 associated with low bone mass in SCD is due to reduced SCFA production by gut microbiota, we performed reciprocal fecal microbiota transplantation (FMT) between healthy control (Ctrl) and SCD mice. uCT and histomorphometry analysis of femur showed decreased bone volume/total volume (BV/TV), trabecular number (Tb.N), osteoblast surface/bone surface (Ob.S/BS), mineralizing surface/ bone surface (MS/BS), inter-label thickness (Ir.L.Th) in SCD mice were significantly improved after receiving Ctrl feces. Bone formation genes Alp, Col1, Runx2, and Dmp1 from SCD mice were significantly decreased and were rescued after FMT from Ctrl feces. Transplantation of Ctrl feces increased the butyrate, valerate, and propionate levels in cecal content of SCD mice. Decreased G-coupled protein receptors 41 and 43 (GPR41 and GPR43) mRNA in tibia and lower IGF1 in bone and serum of SCD mice were partially restored after FMT from Ctrl feces. These data indicate that the healthy gut microbiota of Ctrl mice is protective for SCD bone loss through regulating IGF1 in response to impaired bacterial metabolites SCFAs.

The Insulin-like Growth Factor Signaling Pathway in Breast Cancer: An Elusive Therapeutic Target.

In this review, we provide an overview of the role of the insulin-like growth factor (IGF) signaling pathway in breast cancer and discuss its potential as a therapeutic target. The IGF pathway ligands, IGF-1 and IGF-2, and their receptors, primarily IGF-1R, are important for normal mammary gland biology, and dysregulation of their expression and function drives breast cancer risk and progression through activation of downstream signaling effectors, often in a subtype-dependent manner. The IGF signaling pathway has also been implicated in resistance to current therapeutic strategies, including ER and HER2 targeting drugs. Unfortunately, efforts to target IGF signaling for the treatment of breast cancer have been unsuccessful, due to a number of factors, most significantly the adverse effects of disrupting IGF signaling on normal glucose metabolism. We highlight here the recent discoveries that provide enthusiasm for continuing efforts to target IGF signaling for the treatment of breast cancer patients.

Reduced LYNX1 expression in transcriptome of human iPSC-derived neural progenitors modeling fragile X syndrome.

Lack of FMR1 protein results in fragile X syndrome (FXS), which is the most common inherited intellectual disability syndrome and serves as an excellent model disease to study molecular mechanisms resulting in neuropsychiatric comorbidities. We compared the transcriptomes of human neural progenitors (NPCs) generated from patient-derived induced pluripotent stem cells (iPSCs) of three FXS and three control male donors. Altered expression of RAD51C, PPIL3, GUCY1A2, MYD88, TRAPPC4, LYNX1, and GTF2A1L in FXS NPCs suggested changes related to triplet repeat instability, RNA splicing, testes development, and pathways previously shown to be affected in FXS. LYNX1 is a cholinergic brake of tissue plasminogen activator (tPA)-dependent plasticity, and its reduced expression was consistent with augmented tPA-dependent radial glial process growth in NPCs derived from FXS iPSC lines. There was evidence of human iPSC line donor-dependent variation reflecting potentially phenotypic variation. NPCs derived from an FXS male with concomitant epilepsy expressed differently several epilepsy-related genes, including genes shown to cause the auditory epilepsy phenotype in the murine model of FXS. Functional enrichment analysis highlighted regulation of insulin-like growth factor pathway in NPCs modeling FXS with epilepsy. Our results demonstrated potential of human iPSCs in disease modeling for discovery and development of therapeutic interventions by showing early gene expression changes in FXS iPSC-derived NPCs consistent with the known pathophysiological changes in FXS and by revealing disturbed FXS progenitor growth linked to reduced expression of LYNX1, suggesting dysregulated cholinergic system.

Insulin-like growth factor binding protein 5: Diverse roles in cancer.

Insulin-like growth factor binding proteins (IGFBPs) and the associated signaling components in the insulin-like growth factor (IGF) pathway regulate cell differentiation, proliferation, apoptosis, and adhesion. Of the IGFBPs, insulin-like growth factor binding protein 5 (IGFBP5) is the most evolutionarily conserved with a dynamic range of IGF-dependent and -independent functions, and studies on the actions of IGFBP5 in cancer have been somewhat paradoxical. In cancer, the IGFBPs respond to external stimuli to modulate disease progression and therapeutic responsiveness in a context specific manner. This review discusses the different roles of IGF signaling and IGFBP5 in disease with an emphasis on discoveries within the last twenty years, which underscore a need to clarify the IGF-independent actions of IGFBP5, the impact of its subcellular localization, the differential activities of each of the subdomains, and the response to elements of the tumor microenvironment (TME). Additionally, recent advances addressing the role of IGFBP5 in resistance to cancer therapeutics will be discussed. A better understanding of the contexts in which IGFBP5 functions will facilitate the discovery of new mechanisms of cancer progression that may lead to novel therapeutic opportunities.