Fibroblast Growth Factor 23 Levels Research Articles

The transcription factor BBX regulates phosphate homeostasis through the modulation of FGF23.

Fibroblast growth factor 23 (FGF23) plays an important role in phosphate homeostasis, and increased FGF23 levels result in hypophosphatemia; however, the molecular mechanism underlying increased FGF23 expression has not been fully elucidated. In this study, we found that mice lacking the bobby sox homolog (Bbx-/-) presented increased FGF23 expression and low phosphate levels in the serum and skeletal abnormalities such as a low bone mineral density (BMD) and bone volume (BV), as well as short and weak bones associated with low bone formation. Osteocyte-specific deletion of Bbx using Dmp-1-Cre resulted in similar skeletal abnormalities, elevated serum FGF23 levels, and reduced serum phosphate levels. In Bbx-/- mice, the expression of sodium phosphate cotransporter 2a (Npt2a) and Npt2c in the kidney and Npt2b in the small intestine, which are negatively regulated by FGF23, was downregulated, leading to phosphate excretion/wasting and malabsorption. An in vitro Fgf23 promoter analysis revealed that 1,25-dihydroxyvitamin D3 (1,25(OH)2D3)-induced transactivation of the Fgf23 promoter was significantly inhibited by BBX overexpression, whereas it was increased following Bbx knockdown. Interestingly, 1,25(OH)2D3 induced an interaction of the 1,25(OH)2D3 receptor (VDR) with BBX and downregulated BBX protein levels. Cycloheximide (CHX) only partially downregulated BBX protein levels, indicating that 1,25(OH)2D3 regulates BBX protein stability. Furthermore, the ubiquitination of BBX followed by proteasomal degradation was required for the increase in Fgf23 expression induced by 1,25(OH)2D3. Collectively, our data demonstrate that BBX negatively regulates Fgf23 expression, and consequently, the ubiquitin-dependent proteasomal degradation of BBX is required for FGF23 expression, thereby regulating phosphate homeostasis and bone development in mice.

Depression in childhood to early adulthood and respiratory health in early adulthood

Background Both depression and respiratory disease are common today in young populations. However, little is known about the relationship between them. Aims This study aims to explore the association between depression in childhood to early adulthood and respiratory health outcomes in early adulthood, and the potential underlying mechanisms. Method A prospective study was conducted based on the Swedish BAMSE (Barn, Allergi, Miljö, Stockholm, Epidemiologi [Children, Allergy, Milieu, Stockholm, Epidemiology]) birth cohort (n = 4089). We identified clinically diagnosed depression through the dispensation of antidepressants, using national register data confirmed by self-reported diagnosis. At the 24-year follow-up, respiratory health was assessed via questionnaires and clinical evaluation. Metabolic and inflammatory profiles were analysed to explore potential mechanisms. Results Among the 2994 participants who provided study data, 403 (13.5%) had depression at any time point from around age 10 to 25 years. Depression was associated with higher risks of any chronic bronchitis symptoms (odds ratio = 1.58, 95% CI 1.21–2.06) and respiratory symptoms (odds ratio = 1.41, 95% CI 1.11–1.80) in early adulthood, independent of body mass index (BMI) and smoking status. Compared to individuals without depression, those with depression had a higher fat mass index (FMI (β = 0.48, 95% CI 0.22–0.74)) and increased blood levels of fibroblast growth factor 21 and Interleukin-6 in early adulthood. These markers together with FMI were found to partly mediate the association between depression and respiratory symptoms (total mediation proportion: 19.8 and 15.4%, respectively, P < 0.01). Conclusions Depression in childhood to early adulthood was associated with an increased risk of respiratory ill-health in early adulthood, independently of smoking. Metabolic and inflammatory dysregulations may underlie this link.

Targeted Deletion of Fibroblast Growth Factor 23 Rescues Metabolic Dysregulation of Diet-induced Obesity in Female Mice.

Fibroblast growth factor 23 (FGF23) is a bone-secreted protein widely recognized as a critical regulator of skeletal and mineral metabolism. However, little is known about the nonskeletal production of FGF23 and its role in tissues other than bone. Growing evidence indicates that circulating FGF23 levels rise with a high-fat diet (HFD) and they are positively correlated with body mass index (BMI) in humans. In the present study, we show for the first time that increased circulating FGF23 levels in obese humans correlate with increased expression of adipose Fgf23 and both positively correlate with BMI. To understand the role of adipose-derived Fgf23, we generated adipocyte-specific Fgf23 knockout mice (AdipoqFgf23Δfl/Δfl) using the adiponectin-Cre driver, which targets mature white, beige, and brown adipocytes. Our data show that targeted ablation of Fgf23 in adipocytes prevents HFD-fed female mice from gaining body weight and fat mass while preserving lean mass but has no effect on male mice, indicating the presence of sexual dimorphism. These effects are observed in the absence of changes in food and energy intake. Adipose Fgf23 inactivation also prevents dyslipidemia, hyperglycemia, and hepatic steatosis in female mice. Moreover, these changes are associated with decreased respiratory exchange ratio and increased brown fat Ucp1 expression in knockout mice compared to HFD-fed control mice (Fgf23fl/fl). In conclusion, this is the first study highlighting that targeted inactivation of Fgf23 is a promising therapeutic strategy for weight loss and lean mass preservation in humans.

Elevation of circulating FGF23 in chronic kidney disease promotes atrial fibrosis through the AKT pathway

Abstract Background The relationship between chronic kidney disease (CKD) and atrial fibrillation (AF) remains unclear. Elevated level of fibroblast growth factor 23 (FGF23) is highly associated with increased cardiovascular disease and mortality in patients suffering from CKD. In recent years, studies have shown that FGF23 promotes cardiac hypertrophy through FGFR4, suggesting that FGF23 may be an important bridge between the heart and kidney. Purpose In this study, we sought to use a well-established rat model of CKD to further characterize the effects of CKD on AF and to identify potential drivers of CKD-induced AF. Methods 14 SD rats were randomly selected to undergo 5/6 nephrectomy and fed for 15 weeks to establish a CKD model, while the SHAM group (8 rats) underwent the same surgery without removing kidney tissue. Body weight, blood pressure, renal function, cardiac ultrasound, epicardial electrocardiography, and pathological indices were monitored in both groups. Gene sequencing was performed on the left atria to search for differentially expressed genes. Rat atrial fibroblasts were selected for further mechanism exploration. We chose TGF-β to stimulate fibroblasts to mimic the process of fibrosis in vivo, and then administered FGFR inhibitors to explore the downstream molecular mechanisms. Results Systolic blood pressure and creatinine were elevated in the CKD group. Compared with the SHAM group, the incidence of AF was significantly higher, left atrial diameter was significantly larger, and epicardial electrical markers showed that left atrial electrical conduction velocity was significantly slower and conduction heterogeneity was significantly increased in the CKD group. Pathologic staining of the left atrium showed significant fibrosis in the CKD group. Consistent with previous findings, FGF23 was significantly elevated in CKD rats. Transcriptomic sequencing revealed that FGFR4 expression was significantly upregulated in the left atrium of CKD rats, The results in rat atrial fibroblasts showed that blocking FGFR4 expression inhibited TGF-β-induced fibrosis and was mediated by the AKT pathway. Conclusions The mechanism of CKD-induced AF is that CKD promotes both structural and electrical remodeling of the atria. Further investigation of its possible downstream molecules revealed that elevated FGF23 in the CKD circulation promotes the development of atrial fibrosis by binding to FGFR4 through the AKT pathway.

Assessment of experimental circulating biomarkers in volume and pressure overload: insights from a cohort study

Abstract Introduction Experimental biomarkers including Angiopoietin-2 (ANG2), bone morphogenetic protein 10 (BMP10), fibroblast growth factor 23 (FGF23), and insulin-like growth factor-binding protein 7 (IGFBP7) are hypothesized to reflect cardiac pathophysiological processes that are potentially present in adverse cardiac remodeling in volume or pressure overload. This study aims to elucidate the relationship between these circulating biomarkers and the presence of hemodynamically significant pressure or volume overload and adverse outcomes and compare it to N-terminal pro B-type natriuretic peptide (NT-proBNP). Methods We studied the association between the four experimental circulating biomarkers in patients with pressure or volume overload with reference to none/mild valvular disease in N=1302 of an observational outpatient cardiology cohort. The median age was 63.0 (25th/75th quartile 51.5, 71.4) years, 445 (34.2%) were women. Circulating biomarkers were quantified using a novel antibody-based method. Logistic regression models with cox regression plots were employed to assess the association of each biomarker with the severity of valve disease concerning volume or pressure overload, adjusted for age and sex. Results In the overall population, elevated levels of ANG2, BMP10, FGF23 and IGFB7 were positively associated with the presence of significant volume overload (ANG2: Odds ratio (OR) 1.26 (95% confidence interval (CI) 1.17-1.35), p<0.001; BMP10: OR 2.57 (CI 1.89-3.48), p<0.001; FGF23: OR 1.51 (CI 1.14-1.20), p=0.004; IGFBP7: OR 1.39 (CI 1.14-1.69), p=0.001, NT-proBNP: OR 1.69 (CI 1.47-1.95), p<0.001). No statistically significant association between circulating biomarkers and pressure overload was observed. Over a median follow-up of 4 years, 31 (20.1%) participants died in the group of volume overload and 9 (40.9%) individuals in the group of pressure overload. After multivariable-adjustment, elevated levels of BMP 10 showed a borderline association with an increased risk of all-cause mortality in individuals with volume overload compared to none/mild valvular disease: hazard ratio (HR) 1.51 (CI 0.96- 2.38), p=0.075. Higher concentrations of all biomarkers were predictive of all-cause mortality for both individuals with volume overload and those with none/mild valvular disease (ANG2: HR 3.72 (CI 1.67-8.33), p=0.001; BMP10: HR 1.65 (CI 1.20-2.26), p=0.002; FGF23: HR 2.08 (CI 1.65-2.62), p<0.001; IGFBP7: HR 1.55 (CI 1.25-1.91), p<0.001; NT-proBNP: HR 1.72 (CI 1.47-2.00), p<0.001). Conclusions This study demonstrates that circulating biomarkers involved in distinct pathophysiological pathways of inflammation, fibrosis and calcification are elevated in patients with hemodynamically significant volume overload. Since they are also related to mortality, their clinical role needs to be explored further, also in context with the routine biomarker NT-proBNP.

Causal association of serum calcium, phosphate, vitamin D, parathyroid hormone, and FGF23 with the risk of aortic stenosis

Abstract Aim Disorders of mineral metabolism, including elevated levels of serum calcium, phosphate, 25-hydroxyvitamin D (25OH-VitD), parathyroid hormone (PTH), and fibroblast growth factor 23 (FGF23), have been reported in patients with calcific aortic valve stenosis (CAVS). However, evidence of the causal role of mineral metabolism in CAVS is still lacking. We aimed to investigate the causality between mineral metabolism and CAVS. Methods A systematic pipeline combining Mendelian randomization (MR), Steiger directionality test, colocalization analysis, protein-protein network, and enrichment analysis was applied to investigate the causal effect. Genome-wide association study (GWAS) and protein quantitative trait loci data for mineral metabolism markers were extracted from large-scale meta-analyses. Summary statistics for CAVS were obtained from two independent GWAS datasets as discovery and replication cohorts (n=374,277 and 653,867). Results In MR analysis, genetic mimicry of serum FGF23 elevation was associated with increased CAVS risk [ORdiscovery=3.081 (1.649-5.760), Pdiscovery=4.21×10-4; ORreplication=2.280 (1.461-3.558), Preplication=2.82×10-4] without evidence of reverse causation (Psteiger=7.21×10-98). Strong colocalisation association with CAVS was observed for FGF23 expression in the blood (PP.H4 = 0.96). Additionally, we identified some protein-protein interactions between FGF23 and known CAVS causative genes. Serum calcium, phosphate, 25OH-VitD, and PTH failed to show causal effects on CAVS at Bonferroni-corrected significance (all P>0.05/5=0.01). Conclusions Elevated serum FGF23 level is a causal risk factor for CAVS, and its mechanism of action in CAVS development may be independent of its function in regulating mineral metabolism. Hence, FGF23 may serve as a circulating marker and a promising preventive target for CAVS, warranting further investigation.

Carotid intima-media thickness, fibroblast growth factor 23, and mineral bone disorder in children with chronic kidney disease

BackgroundCarotid intima-media thickness (cIMT) is a measure of atherosclerotic vascular disease and a surrogate biomarker for cardiovascular risk in patients with chronic kidney disease (CKD). Mineral and bone disorders (MBD) are complications of CKD, contributing to vascular calcification and accelerated atherosclerosis. Increased fibroblast growth factor 23 (FGF23)—the earliest detectable serum abnormality associated with CKD-MBD—has been linked with cardiovascular disease in patients with CKD. This study aimed to identify factors and analyze the relationship associated with high cIMT, high FGF23, and poor MBD control in children with CKD.MethodsA cross-sectional study was conducted in Yogyakarta, Indonesia recruiting children with CKD. The correlations and factors between cIMT, FGF23, and MBD were explored.ResultsWe recruited 42 children aged 2–18 years old with CKD stages 2 to 5D. There were no significant correlations between cIMT and factors including advanced CKD, use of dialysis, body mass index, hypertension, anemia, MBD, FGF23 levels, and left ventricular mass index (LVMI). Patients with advanced CKD had poorly controlled anemia, hypertension, and higher LVMI. In multivariate analysis, CKD stages, hypertension stages, the presence of MBD, and LVMI were associated with FGF23 levels (p < 0.05).ConclusionsFGF23 levels increased with CKD progression, and MBD was more prevalent in advanced kidney disease. Elevated FGF23 is potentially associated with increased MBD prevalence in late-stage CKD. A larger study is needed to confirm the factors affecting cIMT in children with CKD.

Vitamin D-Parathyroid Hormone-Fibroblast Growth Factor 23 Axis and Cardiac Remodeling.

Cardiac remodeling is a compensatory adaptive response to chronic heart failure (HF) altering the structure, function, and metabolism of the heart. Many nutritional and metabolic diseases can aggravate the pathophysiological development of cardiac remodeling. Vitamin D deficiency leads to cardiac remodeling by activating the renin-angiotensin-aldosterone system (RAAS), resulting in enhanced inflammation and directly promoting cardiac fibrosis and extracellular matrix deposition. Hyperparathyroidism upregulates protein kinase A or protein kinase C, enhances intracellular calcium influx, promotes oxidative stress, activates RAAS, and increases aldosterone levels, thereby aggravating cardiac remodeling. Besides, fibroblast growth factor 23 (FGF23) plays a direct role in the heart, resulting in ventricular hypertrophy and myocardial fibrosis. Vitamin D deficiency leads to hyperparathyroidism, which in turn increases the level of FGF23. Elevated levels of FGF23 further inhibit vitamin D synthesis. Evidence exists that vitamin D deficiency, hyperparathyroidism, and marked elevations in FGF23 concentration form a vicious cycle and are believed to contribute directly to cardiac remodeling. Therefore, the purpose of this article is to introduce the specific effects of the above substances on the heart and to explain the significance of understanding the vitamin D-parathyroid hormone-FGF23 axis in improving or even reversing cardiac remodeling, thus contributing to the treatment of patients with HF.

Improvement of Bone Metabolism in Prepubertal Girls with Turner Syndrome Following Long-term Pegylated Growth Hormone Treatment.

The study aims to assess the improvement in bone metabolism in prepubertal girls with Turner Syndrome (TS) after long-term polyethylene glycol recombinant human Growth Hormone (PEG-rhGH) treatment. A 12-month longitudinal prospective study was conducted with 28 prepubertal girls diagnosed with TS. Participants were divided into two groups: 18 received PEG-rhGH therapy (0.1-0.25 mg/kg/week) and 10 did not. Anthropometric measurements, bone turnover markers (BTMs), and serum levels of IGF-1, calcium, and phosphate were collected at baseline and after 12 months. BTMs included bone alkaline phosphatase (BAP), Type I collagen propeptide (CICP), Type I collagen telopeptide (CTX), and fibroblast growth factor 23 (FGF23). After 12 months of PEG-rhGH therapy, the treatment group showed significant increases in growth velocity (GV) and height standard deviation scores (HtSDS). Serum IGF-1 levels increased rapidly within one month and remained elevated. BTMs indicated enhanced bone formation, significantly increasing BAP and CICP, while CTX levels remained low. FGF23 levels initially rose slightly but declined below baseline by 12 months. Elevated blood phosphate levels were observed. PEG-rhGH therapy in children with TS significantly improves linear growth and enhances bone formation markers, benefiting bone metabolism.

Evaluation of alpha Klotho and fibroblast growth factor-23 levels in Iraqi patients with Graves’ disease

Background &amp; Objective: Graves’ disease (GD) is an autoimmune condition that targets the thyroid gland, resulting in excessive stimulation and synthesis of thyroid hormones. Excessive synthesis of these hormones can lead to symptoms such as loss of body weight, accelerated heart rate, irritability, reduced tolerance to heat, and excessive perspiration. Alpha-Klotho (KL), a protein crucial for physiological processes, is also involved in GD. The defective immunological condition of GD patients may increase Klotho expression, and the enhanced expression of fibroblast growth factor-23 (FGF23) in GD may be linked to the disease pathophysiology. We investigated serum levels of KL and FGF23 in Iraqi patients with Graves’ disease, analyzing correlations with clinical status and evaluating their potential as biomarkers for disease activity. Methodology: We conducted this cross-sectional study at The National Diabetes Center, Mustansiriyah University, between December 2022 and April 2023. The study involved 103 patients diagnosed with GD, and 103 patients, aged 21-70 y, as a control group. Patients with multinodular goiter, single thyroid nodules, thyroiditis, pregnant women, and those on medications or oral contraceptives, were excluded. Result: clinical significance of FGF23 and Klotho (KL) levels in patients with Graves’ disease (GD) compared to a control group. Results indicate that the median of KL levels are significantly higher in GD patients (KL = 6.31) compared to the control group (KL = 2.40), with a highly significant difference (P &lt; 0.001). In contrast, differences in median of FGF23 levels between GD patients (149) and controls (86.05) were not statistically significant (P = 0.07). Furthermore, KL levels were significantly higher in hyperthyroid patients compared to other thyroid statuses (P = 0.023), while FGF23 levels did not significantly differ across thyroid statuses (P = 0.255). Additionally, the study found a strong correlation between TRAb levels and both KL (r = 0.291, P &lt; 0.001) and FGF23 (r = 0.211, P = 0.003), and between KL and FGF23 directly (r = 0.412, P &lt; 0.001). These findings suggest that while KL may be a significant biomarker in GD, FGF23 relevance appears limited in this context. Conclusion: In Graves’ Disease patients have significantly higher levels of KL and FGF23 compared to controls, suggesting a distinct pathophysiological role for these biomarkers in mineral homeostasis and thyroid hormone regulation. Abbreviations: AITD - Autoimmune thyroid diseases; KL - Alpha-Klotho; FGF23 - fibroblast growth factor-23; GD - Graves’ disease; HT - Hashimoto's thyroiditis; IGF-1R - Insulin-like Growth Factor-1 Receptor; Keywords: Autoimmune Thyroid Disorders, Hyperthyroidism, Graves’ disease, Alpha-Klotho Citation: Rashid MF, Alammar HAJ, Rahmah AM. Evaluation of alpha Klotho and fibroblast growth factor-23 levels in Iraqi patients with Graves’ disease. Anaesth. pain intensive care 2024;28(5):836−841. DOI: 10.35975/apic.v28i5.2567 Received: June 16, 2024; Reviewed: July 07, 2024; Accepted: July 18, 2024

6990 Vitamin D Supplementation in Primary Hyperparathyroidism: Effects on 1,25(OH)Vitamin D and FGF23 Levels

Abstract Disclosure: S.G. Pallone: None. M. Ohe: None. L.D. Santos: None. I.O. Nakaguma: None. I.S. Kunii: None. R.E. Silva: None. S.S. Maeda: None. C.M. Brandao: None. J.G. Vieira: None. M. Lazaretti-Castro: None. Background: Primary hyperparathyroidism (PHPT) is a condition characterized by high levels of PTH in the presence of hypercalcemia. Vitamin D deficiency has been associated with more severe presentations. Our aim was to evaluate the effects of Vitamin D supplementation on mineral homeostasis and related hormones in individuals with PHPT compared to controls without PHPT. Materials and methods: Individuals with and without PHPT received 14,000 IU/week of oral vitamin D3 for 12 weeks. At baseline and endpoint, blood samples were collected to measure 1,25(OH)2 vitamin D (1,25(OH)2D), intact Fibroblast Growth Factor 23 (FGF23), 25-hydroxyvitamin D (25OHD), Parathormon (PTH), total calcium (tCa), phosphorus and other biochemical markers. The intact FGF23 was measured using an automated Diasorin LIAISON kit. The 1,25(OH)2D measurement was performed using liquid chromatography and mass spectrometry (LC-MS/MS). Results: 70 PHPT patients and 75 healthy individuals (CTRL) were included, and 55 PHPT and 64 CTRL completed the 12-week protocol. At baseline, tCa, PTH, 1,25(OH)2D, and intact FGF23 concentrations were significantly higher in PHTP, with no difference in 25OHD levels. After the intervention, the 25OHD levels increased significantly in both groups (PHPT: 22.6.9±6.1 to 31.5±6.8; CTRL: 20.3±5.7 to 32.5±6.4 ng/mL, p&amp;lt;0.001). There was significative increase in intact FGF23 levels in both groups (PHPT: 47.9±27.1 to 76.3±33.3; CTRL: 40.5±13.9 to 59.8±19.8 pg/mL, p&amp;lt;0.001). After the vitamin D replacement, the tubular reabsorption of phosphate (TRP) was significantly reduced in both groups (PHPT: 85.0±7.4% to 83.6±7.75% CTRL: 89.5±4.5% to 88.7±4.8%, p=0.031), without changes in serum phosphorus levels, possibly indicating phosphaturic response to the intervention. Moreover, this decrease of TRP was positively correlated to the increment of FGF23 in the PHPT group. A paradoxical decrease in 1,25(OH)2D levels after vitamin D supplementation was observed in both groups (PHPT: 94.8±34.6 to 68.9±25.3; CTRL: 68.7±23.5 to 56.4±20.7 pg/mL, p&amp;lt;0.001). The reduction of 1,25(OH) 2 D was inversely correlated with the elevation of FGF23 in both groups (r=-0.302, p=0.028). In both groups, no changes in tCa were observed (PHPT: from 11.02±0.9 to 11.1±0.8; CTRL: 9.6±0.3 to 9.6±0.3 pg/mL, p=0.153), as the same for urinary calcium (p=0.534) and PTH measurements (p=0.516). Conclusion: The weekly administration of 14,000 IU of Vitamin D3 was safe and the increase in 25OHD after supplementation did not change the serum or urinary calcium levels in adults with and without PHPT. In both groups, it was observed a paradoxical decrease in 1,25(OH)2D levels after supplementation, which was associated with significant increase in intact FGF23 levels. This effect can maybe explain the safety response on calcium levels in face of vitamin D supplementation among PHPT patients. Presentation: 6/2/2024

7345 Study on the correlation between the levels of myokines and metabolic abnormality in obese children

Abstract Disclosure: L. Ouyang: None. M. Li: None. F. Yang: None. Objective: There are limited drug options to treat childhood obesity. Studies have found that myokines play an important role in the mechanism of exercise in the treatment of obesity. However, the correlation between myokines and metabolic abnormalities in obese children is still unclear. The purpose of this study is to analyze the correlation between the levels of myokines and metabolic abnormalities in obese children to provide the basis for the future application of myokines in childhood obesity. Methods: 41 obese children who visited the pediatric clinic of our hospital from March to October 2022 were enrolled, and 11 healthy non-obese children who had a regular physical examination in the pediatric clinic during the same period were enrolled. Basic information, anthropological indicators and biochemical indicators were collected. Human myokine magnetic bead panel was used to detect serum myokine levels including irisin, FGF21, BDNF, LIF, MSTN, IL 6, and IL 15. Difference analysis, rank sum test and Spearman analysis were used to conduct the correlation between the levels of myokines and metabolic abnormalities in obese children. Results: We found that the BMI-SDS and body fat rate of obese children with abnormal metabolism was higher than those with normal metabolism status(p&amp;lt;0.05). Children with abnormal glucose metabolism had an increased risk of abnormal lipid metabolism and hyperuricemia(p &amp;lt; 0.05), and children with abnormal lipid metabolism had an increased risk of hyperuricemia and hypertension(p&amp;lt;0.05). The obese children with abnormal glucose and lipid metabolism had an increased risk of abnormal purine metabolism. The levels of leukemia inhibitory factor and brain-derived neurotrophic factor in obese children were significantly higher than those in non-obese children (p&amp;lt;0.05), and the level of fibroblast growth factor 21 in obese children with abnormal metabolism was significantly higher than that in children with normal metabolism (p&amp;lt;0.05), respectively. There was a significant positive correlation between BMI-SDS and the levels of irisin, leukemia inhibitory factor and brain-derived neurotrophic factor (r=0.361, 0.368, 0.343, p=0.009, 0.007, 0.013, respectively). There was a significant positive correlation between irisin, BDNF, LIF, MSTN and IL 6, and between FGF21 and irisin, MSTN, IL 6 in children (p &amp;lt; 0.05). Conclusions: With the increase in BMI, the risk of metabolic abnormalities in obese children increases. Obese children with one kind of metabolic abnormality are prone to merge with other metabolic abnormalities. The levels of leukemia inhibitory factor, fibroblast growth factor 21, irisin, brain-derived neurotrophic factor, and other myokine in obese children and obese children with abnormal metabolism are different from those in non-obese children and obese children with normal metabolism respectively, and there is interaction between myokines. Presentation: 6/1/2024

Serum galectin-3 and fibroblast growth factor-23 levels in relation with type 2 diabetes and cardiovascular risk

Serum galectin-3 and fibroblast growth factor-23 levels in relation with type 2 diabetes and cardiovascular risk

Human milk feeding practices and serum immune profiles of one-year-old infants in the CHILD birth cohort study

Breastfeeding and human milk consumption are associated with immune system development; however, the underlying mechanisms and the impact of different infant feeding practices are unclear. This study aimed to investigate how current human milk feeding (HMF) status is related to infant immune biomarker profiles, and explore relationships with HMF history (i.e., duration, exclusivity, and method: directly from the breast, or pumped and bottled). This observational birth cohort study involved 605 infants from the Canadian CHILD Cohort Study. Infant feeding was captured from hospital birth records and parent questionnaires. Ninety-two biomarkers reflecting immune system activity and development were measured in serum collected at one year (12.6±1.4 months) using the Olink Target 96 Inflammation panel. Associations were determined using multivariable regression (adjusted for sex, time until blood sample centrifugation, and study site). Nearly half (42.6%) of infants were still HMF at the time of blood sampling. Compared to non-HMF infants, HMF infants had higher levels of serum Fibroblast Growth Factor 21 (FGF-21, adjusted standardized β-coefficient=0.56; 95%CI=0.41,0.72), Cluster of Differentiation 244 (CD244, β=0.35; 0.19,0.50), Chemokine Ligand 6 (CXCL6, β=0.34; 0.18,0.50), and Chemokine Ligand 20 (CCL20, β=0.26; 0.09,0.42), and lower Extracellular Newly Identified Receptor for Advanced Glycation End-Products Binding Protein (EN-RAGE, β=-0.16; -0.29,-0.03). Among non-HMF infants, serum Interleukin 7 (IL-7) had a marginally positive association with past HMF duration (β=0.05; 0.02,0.08) that persisted for up to five months post-HMF cessation. Exclusive HMF duration and HMF method (at three months of age) were not associated with any biomarkers. Current HMF status and (to a lesser extent) HMF history are associated with several inflammation-associated biomarkers in one-year-old infants. These results provide new evidence that HMF impacts immune activity and development and suggest hypotheses about the underlying mechanisms. They also highlight the importance of including current HMF status in immune-system-focused infant serum proteomic studies.

The Role of Omentin-1 and Fibroblast Growth Factor-23 in Iraqi Patients with Prostate Cancer during Chemotherapy

Background: Omentin-1 is mainly expressed in stromal vascular cells of adipose tissue and can also be expressed in airway goblet cells, mesothelial cells, and vascular cells. Fibroblast growth factor 23 (FGF-23), generated by bone cells, regulates phosphate and vitamin D metabolism by regulating phosphate reabsorption in the kidneys and inhibiting vitamin D activation. Vitamin D is a fat-soluble vitamin that regulates calcium absorption, bone health, and immunological function. Prostate cancer is a significant health concern for men worldwide. Several studies demonstrated a link between these variables and cancer as they exert important anti-inflammatory, antioxidative, and anti-cancer functions. Objectives: To assess the impact of Omentin and FGF-23 biochemical functions, as well as the anti-cancer properties of vitamin D. Subjects and methods: This is a case-control study on serum samples collected from Iraqi prostate cancer patients after receiving chemotherapy at Al Amal Center in Imam Hussein Medical City in Karbala between November 2022 to May 2023. The serum samples were collected from two groups: control group consisted of 30 healthy males. Patient group consisted of 30 prostate cancer patients after receiving chemotherapy, both groups aged 45 – 80 years. The two groups were matched for body mass index. ELISA technology was used to estimate serum levels of the aforementioned biochemical parameters with vitamin D. Results: patient group had a significantly higher FGF-23 level than control group (309.5±41.65) versus (163.1±22.4) (p&lt;0.001). On the other hand, Irisin, Omentin and Vitamin D mean serum concentrations were significantly lower in-patient group (15.2±4.24), (13.8±4.28) and (4.4±0.69) (p&lt;0.001), respectively, compared to control group (60.8±3.5), (38.8±6.59), and (18.9±2.36), respectively. (ROC) curve analysis identified the best AUC values of FGF-23, Omentin, and Vitamin D (0.995, 0.959, 0.937), respectively, which suggests a high level of accuracy. Conclusions: These parameters may serve as critical indicators for prostate cancer patients and their disease progress. Vitamin D insufficiency is a risk factor for these individuals.

Increased Cadmium Load, Vitamin D Deficiency, and Elevated FGF23 Levels as Pathophysiological Factors Potentially Linked to the Onset of Acute Lymphoblastic Leukemia: A Review.

The preventability of acute lymphocytic leukemia during childhood is currently receiving great attention, as it is one of the most common cancers in children. Among the known risk factors so far are those affecting the development of gut microbiota, such as a short duration or absence of breastfeeding, cesarean section, a diet lacking in short-chain fatty acids (SCFAs), the use of antibiotics, absence of infection during infancy, and lack of pets, among other factors. Namely, it has been shown that iron deficiency anemia (IDA) and lack of vitamin D may cause intestinal dysbiosis, while at the same time, both increase the risk of hematological malignancies. The presence of IDA and vitamin D deficiency have been shown to lead to a decreased proportion of Firmicutes in stool, which could, as a consequence, lead to a deficit of butyrate. Moreover, children with IDA have increased blood concentrations of cadmium, which induces systemic inflammation and is linked to the onset of an inflammatory microenvironment in the bone marrow. Finally, IDA and Cd exposure increase fibroblast growth factor 23 (FGF23) blood levels, which in turn suppresses vitamin D synthesis. A lack of vitamin D has been associated with a higher risk of ALL onset. In brief, as presented in this review, there are three independent ways in which IDA increases the risk of acute lymphocytic leukemia (ALL) appearance. These are: intestinal dysbiosis, disruption of vitamin D synthesis, and an increased Cd load, which has been linked to systemic inflammation. All of the aforementioned factors could generate the appearance of a second mutation, such as ETV6/RUNX1 (TEL-AML), leading to mutation homozygosity and the onset of disease. ALL has been observed in both IDA and thalassemia. However, as IDA is the most common type of anemia and the majority of published data pertains to it, we will focus on IDA in this review.

Prostaglandin E2 signaling through prostaglandin E receptor subtype 2 and Nurr1 induces fibroblast growth factor 23 production

Bone cells produce fibroblast growth factor 23 (FGF23), a hormone regulating renal phosphate and vitamin D homeostasis, and a paracrine factor produced in further tissues. Chronic kidney disease and cardiovascular disorders are associated with early elevations of plasma FGF23 levels associated with clinical outcomes. FGF23 production is dependent on many conditions including inflammation. Prostaglandin E2 (PGE2) is a major eicosanoid with a broad role in pain, inflammation, and fever. Moreover, it regulates renal blood flow, renin secretion, natriuresis as well as bone formation through prostaglandin E receptor 2 (EP2). Here, we studied the role of PGE2 and its signaling for the production of FGF23. Osteoblast-like UMR-106 cells were exposed to EP receptor agonists, antagonists or RNAi. Wild type and EP2 knockout mice were treated with stable EP2 agonist misoprostol. Fgf23 or Nurr1 gene expression was determined by quantitative real-time PCR, hormone and further blood parameters by enzyme-linked immunosorbent assay and colorimetric methods. PGE2 and EP2 agonists misoprostol and butaprost enhanced FGF23 production in UMR-106 cells, effects mediated by EP2 and transcription factor Nurr1. A single dose of misoprostol up-regulated bone Fgf23 expression and FGF23 serum levels in wild type mice with subtle effects on parameters of mineral metabolism only. Compared to wild type mice, the FGF23 effect of misoprostol was significantly lower in EP2-deficient mice. To conclude, PGE2 signaling through EP2 and Nurr1 induces FGF23 production. Given the broad physiological and pathophysiological implications of PGE2 signaling, this effect is likely of clinical relevance.

Exploring the impact of inflammatory cytokines on alcoholic liver disease: a Mendelian randomization study with bioinformatics insights into potential biological mechanisms

ABSTRACT Background: Alcoholic liver disease (ALD) significantly contributes to global morbidity and mortality. The role of inflammatory cytokines in alcohol-induced liver injury is pivotal yet not fully elucidated. Objectives: To establish a causal link between inflammatory cytokines and ALD using a Mendelian Randomization (MR) framework. Methods: This MR study utilized genome-wide significant variants as instrumental variables (IVs) for assessing the relationship between inflammatory cytokines and ALD risk, focusing on individuals of European descent. The approach was supported by comprehensive sensitivity analyses and augmented by bioinformatics tools including differential gene expression, protein-protein interactions (PPI), Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis, and analysis of immune cell infiltration. Results: Our findings reveal that increased levels of stem cell growth factor beta (SCGF-β, beta = 0.141, p = .032) and interleukin-7 (IL-7, beta = 0.311, p = .002) are associated with heightened ALD risk, whereas higher levels of macrophage inflammatory protein-1α (MIP-1α, beta = -0.396, p = .004) and basic fibroblast growth factor (bFGF, beta = -0.628, p = .008) are linked to reduced risk. The sensitivity analyses support these robust causal relationships. Bioinformatics analyses around inflammatory cytokine-associated SNP loci suggest multiple pathways through which cytokines influence ALD. Conclusion: The genetic evidence from this study convincingly demonstrates that certain inflammatory cytokines play directional roles in ALD pathogenesis. These findings provide insights into the complex biological pathways involved and underscore the potential for developing targeted therapies that modulate these inflammatory responses, ultimately improving clinical outcomes for ALD patients.

Long-Term Efficacy and Safety of Upacicalcet in Japanese Hemodialysis Patients with Secondary Hyperparathyroidism: Open-Label 52-Week Study

Plain Language SummaryCalcimimetics are widely used for the treatment of secondary hyperparathyroidism (SHPT) in hemodialysis (HD) patients. However, conventional calcimimetics have risks of upper gastrointestinal disturbances and hypocalcemia. Upacicalcet, a novel intravenous calcimimetic, is expected to reduce these risks. To assess the long-term efficacy and safety of upacicalcet, a phase 3 open-label, 52-week study in HD patients with SHPT was conducted in Japan. A total of 157 Japanese HD patients with serum intact parathyroid hormone (iPTH) levels >240 pg/mL and corrected calcium (cCa) levels ≥8.4 mg/dL were enrolled. Of those, 138 completed the 52-week upacicalcet treatment. Upacicalcet achieved the target serum iPTH level (60–240 pg/mL) in 94.2% of patients at 52 weeks. Moreover, upacicalcet decreased bone metabolism markers, intact fibroblast growth factor-23 levels, and parathyroid gland volume. Upacicalcet reduced corrected calcium-phosphate product levels even in patients with mild SHPT, i.e., serum iPTH level ≤300 pg/mL. Upacicalcet caused neither symptomatic hypocalcemia nor cCa levels <7.5 mg/dL despite the negligible increase of concomitant vitamin D receptor activators and calcium carbonate. Gastrointestinal symptoms leading to upacicalcet dose reduction were not occurred. In conclusion, upacicalcet stably reduced the serum iPTH levels in HD patients with mild-to-severe SHPT, with few safety concerns. Serum cCa and P levels were well controlled, with a low incidence of hypocalcemia. Upacicalcet is a novel calcimimetic that may provide safe and appropriate long-term treatment of SHPT.

Phosphaturic mesenchymal tumor demonstrated by 68Ga-DOTATATE PET/CT in a patient: a case report

Tumor-induced osteomalacia (TIO) is a paraneoplastic syndrome caused by abnormally high levels of fibroblast growth factor 23 (FGF-23), most commonly produced and secreted by small phosphaturic mesenchymal tumors (PMT). These tumors can show various anatomic locations throughout soft tissue and bone. The presence of the tumor itself rarely causes symptoms. Nonspecific symptoms such as muscle weakness and musculoskeletal pain are related to the developing hypophosphatemia and osteomalacia as a secondary effect of the increased circulating levels of FGF-23. Therefore, as the initial presentation can mimic a wide range of metabolic or inflammatory diseases, proper diagnosis is often delayed. Localization of the tumor is crucial, as its complete surgical resection is the only curative treatment. Whole-body functional imaging targeting the overexpression of somatostatin receptors (SSTR) on the surface of the PMT cells, is a highly specific and sensitive imaging method to detect the primary tumor site. Here, we discuss a case of TIO in a patient initially presenting with symptoms of inflammatory spondyloarthritis. SSTR positron emission imaging using 68Ga-DOTATATE was central in diagnosing and localizing the primary tumor.