Fibroblast Growth Factor 23 Levels Research Articles

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.

LTBP2 down-regulated FGF2 to repress vascular smooth muscle cell proliferation and vascular remodeling in a rat model of intracranial aneurysm

This work probed into the role of latent transforming growth factor beta binding protein 2 (LTBP2) in intracranial aneurysm (IA). The rats underwent IA modeling and then stereotactic injection of short hairpin RNA against LTBP2 (shLTBP2). Hematoxylin-eosin (HE) staining was employed to assess IA model and vascular remodeling. Rat vascular smooth muscle cells (VSMCs) were transfected with shLTBP2, LTBP2 overexpression plasmid and fibroblast growth factor 2 (FGF2) overexpression plasmid. The mRNA and protein expressions of LTBP2, FGF2 and mitochondrial apoptosis-related factors (Caspase-3, Cyt-c, Mcl-1) were tested through qRT-PCR and Western blot. Cell viability, proliferation and apoptosis were examined by cell counting kit-8, EdU assay and flow cytometry. The up-regulated LTBP2 and down-regulated FGF2 were detected in IA rats. LTBP2 knockdown promoted vascular remodeling and Mcl-1 level, and restrained cell apoptosis and expressions of Caspase-3 and Cyt-c in IA model rats. Moreover, LTBP2 knockdown potentiated cell viability, proliferation and FGF2 level, and repressed apoptosis in rat VSMCs, while overexpressed LTBP2 exerted opposite effects. FGF2 overexpression promoted proliferation and Mcl-1 level, and inhibited apoptosis and expressions of Caspase-3 and Cyt-c in rat VSMCs, which also reversed the effects of overexpressed LTBP2 on these aspects. Collectively, LTBP2 down-regulates FGF2 to repress VSMCs proliferation and vascular remodeling in an IA rat model.

Effect of polydeoxyribonucleotide and polynucleotide on rotator cuff healing and fatty infiltration in a diabetic rat model

Failure rate after chronic rotator cuff repair is considerably high. Moreover, diabetes mellitus is known as a compromising factor of rotator cuff tear. The effect of Polydeoxyribonucleotide (PDRN) and polynucleotide (PN) on tendon healing and fatty infiltration is unclear as tissue regeneration activator in diabetic state. Therefore, a diabetic rat model with chronic rotator cuff tear was made for mechanical, histologic and blood tests. In the animal study using a diabetic rat cuff repair model, the administration of PDRN and PN increased the load to failure of repaired cuffs and improved tendon healing and decreased fatty infiltration. Also, the plasma levels of vascular endothelial growth factor and fibroblast growth factor were elevated in PDRN and PN administrated groups. We concluded that PDRN and PN appear to boost tendon recovery and reduce the presence of fatty infiltration following cuff repair in diabetic state. Also, PN showed a later onset and a longer duration than PDRN associated with the mean plasma growth factors.

Second-line Treatment Strategy in Unresectable Hepatocellular Carcinoma After First-line Atezolizumab Plus Bevacizumab.

Atezolizumab plus beva-cizumab (AteBev) are an integral part of first-line therapy for unresectable hepatocellular carcinoma (uHCC), whereas no second-line regimen has been developed for these patients. This study evaluated the efficacy of second-line therapy for uHCC following AteBev treatment. Sixty uHCC patients who were administered AteBev therapy were included in the study. Dynamic computed tomography was conducted after 6, 9, and 12 weeks, and blood tests were performed at baseline and after three weeks. After six weeks of AteBev therapy, 19 patients experienced partial response (PR), 12 had stable disease (SD), and 29 exhibited progressive disease (PD), with an overall response rate (ORR) of 31.7%. Of the 21 patients treated with lenvatinib as second-line treatment, one dropped out, nine experienced a compete response (CR) or PR, and 11 had SD or PD, resulting in an ORR of 45.0%. Serum levels of fibroblast growth factors (FGF)-19 increased substantially following lenvatinib therapy in the CR+PR group, although the levels decreased significantly in the SD+PD group. Soluble FGF-R4 levels did not differ significantly between the CR+PR group and the SD+PD group when assessed before and after lenvatinib treatment. Lenvatinib is useful as second-line treatment after Ate/Bev for uHCC patients who do not response to Ate/Bev treatment. Changes in serum FGF-19 levels after three weeks of AteBev therapy may serve as a biomarker for selecting lenvatinib as second-line therapy.

Fibroblast growth factor 2 enhances BMSC stemness through ITGA2-dependent PI3K/AKT pathway activation.

Bone marrow-derived mesenchymal stem cells (BMSC) are promising cellular reservoirs for treating degenerative diseases, tissue injuries, and immune system disorders. However, the stemness of BMSCs tends to decrease during in vitro cultivation, thereby restricting their efficacy in clinical applications. Consequently, investigating strategies that bolster the preservation of BMSC stemness and maximize therapeutic potential is necessary. Transcriptomic and single-cell sequencing methodologies were used to perform a comprehensive examination of BMSCs with the objective of substantiating the pivotal involvement of fibroblast growth factor 2 (FGF2) and integrin alpha 2 (ITGA2) in stemness regulation. To investigate the impact of these genes on the BMSC stemness in vitro, experimental approaches involving loss and gain of function were implemented. These approaches encompassed the modulation of FGF2 and ITGA2 expression levels via small interfering RNA and overexpression plasmids. Furthermore, we examined their influence on the proliferation and differentiation capacities of BMSCs, along with the expression of stemness markers, including octamer-binding transcription factor 4, Nanog homeobox, and sex determining region Y-box 2. Transcriptomic analyzes successfully identified FGF2 and ITGA2 as pivotal genes responsible for regulating the stemness of BMSCs. Subsequent single-cell sequencing revealed that elevated FGF2 and ITGA2 expression levels within specific stem cell subpopulations are closely associated with stemness maintenance. Moreover, additional in vitro experiments have convincingly demonstrated that FGF2 effectively enhances the BMSC stemness by upregulating ITGA2 expression, a process mediated by the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway. This conclusion was supported by the observed upregulation of stemness markers following the induction of FGF2 and ITGA2. Moreover, administration of the BEZ235 pathway inhibitor resulted in the repression of stemness transcription factors, suggesting the substantial involvement of the PI3K/AKT pathway in stemness preservation facilitated by FGF2 and ITGA2. This study elucidates the involvement of FGF2 in augmenting BMSC stemness by modulating ITGA2 and activating the PI3K/AKT pathway. These findings offer valuable contributions to stem cell biology and emphasize the potential of manipulating FGF2 and ITGA2 to optimize BMSCs for therapeutic purposes.

Alleviating effects of guar gum on high-fat diet-induced liver injury in common carp (Cyprinus carpio)

This research aimed to determine the effect of dietary guar gum inclusion in high-lipid diets on the liver health of common carp (Cyprinus carpio). Four high-fat diets (10 % crude lipid) containing 0 % (HF), 0.3 % (HFG0.3), 1 % (HFG1), and 3 % (HFG3) of guar gum and a normal-lipid diet (5 % crude lipid; Control) were formulated. The tested diets were evenly and randomly distributed to fifteen tanks, with each tank containing thirty fish (4.53 ± 0.05 g). Fish were fed until apparent satiation for eight weeks. Compared to HF, diets HFG0.3, HFG1, and HFG3 significantly improved feed efficiency, with the HFG0.3 diet enhancing weight gain rate and specific growth rate. The results indicated that HF induced gut dysbiosis, hepatic lipid accumulation, oxidative stress, inflammation, and disturbance in hepatic lipid and cholesterol metabolism. Compared to the HF diet, diets HFG0.3, HFG1, and HFG3 substantially decreased hepatic lipid accumulation and malonaldehyde content, increased catalase activity and the expression of AMP-activated protein kinase (AMPKα2), peroxisomal proliferator-activated receptor alpha (PPARα), cholesterol 7alpha-hydroxylase, and decreased the expression of interleukin-1β (IL-1β). Moreover, the HFG0.3 and HFG1 diets dramatically increased nuclear factor erythroid 2-related factor 2 and liver X receptor expression and decreased protein carbonyl contents and expression of IL-8, nuclear factor kappa B (NF-κB p65), and tumor necrosis factor α. Furthermore, the HFG1 diet significantly increased carnitine palmitoyltransferase 1 and peroxisomal proliferator-activated receptor gamma coactivator 1 expression and reduced expression levels of fibroblast growth factor 19, farnesoid X receptor, and sterol regulatory element-binding protein type 1. The linear discriminant analysis effect size (LEfSe) analysis showed that HFG 0.3 and HFG1 substantially increased the enrichment of beneficial microbiota (e.g., lactic acid bacteria, Cetobacterium, and Fusobacterial) and decreased the enrichment of harmful microbiota (e.g., Proteobacteria, Acinetobacter, and Pseudomonas) compared to HF. These results suggested that guar gum can mitigate high-fat diet-induced liver damage in fish.

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

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. In this study, we employed a systematic pipeline combining Mendelian randomization (MR), Steiger directionality test, colocalization analysis, protein-protein network, and enrichment analysis to investigate the causal effect of mineral metabolism on CAVS. 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). 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-associated 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). In conclusion, elevated serum FGF23 level may act as 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.

Dihydroartemisinin inhibited vasculogenic mimicry in gastric cancer through the FGF2/FGFR1 signaling pathway

Vasculogenic mimicry (VM) is a novel model for supplying blood to multiple tumors, including gastric cancer (GC), and is a potential target for its treatment. Dihydroartemisinin (DHA) is a potential natural antitumor substance that inhibits the progression of tumors in many ways. The research aimed to evaluate the impact of DHA on VM formation and its mechanisms. The IC50 of DHA, DHA's effect on proliferation, invasion, and migration in GC cells and VM formation in both cell and animal models were determined through wound healing, MTT, EdU, colony formation, and Transwell assays. Genomics was employed to identify genes related to DHA inhibition of VM formation, and to analyze their relationship to VM formation. qRT‒PCR and western blot (WB) analysis were carried out to analyze the changes in protein and mRNA levels after DHA treatment and the changes in VM-associated protein biomarkers after blocking target gene-related pathways. The mechanism by which DHA inhibits VM in GC was elucidated in vivo. DHA reduced the invasion, proliferation, and migration of GC cells and inhibited VM in cells and in vivo. A total of 220 DEGs were identified in the DHA-treated HGC-27 cells. Among the 146 downregulated genes, fibroblast growth Factor 2 (FGF2) was most closely associated with angiogenesis and VM. The level of FGF2 in GC tissues with VM was markedly greater than in VM lacking tissues. Treatment with DHA or FGFR1 blockade suppressed VM formation and reduced VM-related biomarker proteins. DHA suppressed tumor progression and VM formation by reducing FGF2 in xenograft mouse models. Per our knowledge, this is the first study to demonstrate the inhibitory effect of DHA on VM, providing a novel strategy for the treatment of GC.

Design and decoration of copper nanoparticles into lignosulfonate-starch bionanocomposite: Characterization and evaluation of its therapeutic properties on burn wound

In this report, eco-friendly synthesis for the production of copper nanoparticles by employing the sodium lignosulfonate (NaLS) mixed starch composite (NaLS-Starch/Cu NPs). NaLS-Starch mixed hydrogel has notable reducing and stabilizing potential for preparation of Cu nanoparticles. Characterization of NaLS-Starch/Cu NPs bionanocomposite was subjected to analysis of spectroscopic and microscopic techniques, including FE-SEM, TEM, EDS-elemental mapping, particle size distribution, XRD and ICP. TEM images displayed the spherical structured NaLS-Starch/Cu NPs, averaging 5–10 nm size. NaLS-Starch/Cu NPs were applied to cure the induced burn wounds in 60 Wistar rats. A group was considered as control group. The animals were treated with basal, tetracycline 3 % and NaLS-Starch/Cu NPs 3 % for 30 days and the treatment efficacy was determined according to the burn wound area reduction and molecular and histological characteristics. Taken together, these results support therapeutic use of NaLS-Starch/Cu NPs as potent ointment that may be proposed for burn wound healing. NaLS-Starch/Cu NPs ointment increased the levels of platelet-derived growth factors (PDGF) and fibroblast growth factor (bFGF). The mean wound surface, in all groups treated by NaLS-Starch/Cu NPs was larger than control group.

Evaluating Fibroblast Growth Factor 21 (FGF21) Levels Post-Gastric Sleeve Surgery in Obese Patients.

Background and objectives Obesity is a major global health concern linked with increased risk of chronic diseases. This study aimed to assess the levels of fibroblast growth factor 21 (FGF21) insubjects with obesity after gastric sleeve surgery and explore its correlation with lipid and glycemic parameters. Methods This retrospective cohort study included 28 obese male subjects aged 25 to 50 years, undergoing gastric sleeve surgery. Plasma levels of FGF21 were measured by enzyme-linked immunosorbent assay (ELISA) before and six to 12 months after surgery. Other parameters including body mass index (BMI), fasting glucose, lipid profile, and insulin were also assessedand homeostatic model assessment (HOMA) was used to estimate insulin resistance. Results There was a significant increase in systemic FGF21 levels after surgery (45.12 vs. 126.16 pg/mL, p = 0.007). There was also a notable reduction in BMI (51.55 vs. 39.14, p < 0.001), insulin levels (20.06 vs. 8.85 mIU/L, p < 0.001), HOMA scores (6.94 to 2.49, p < 0.001), and glucose levels (7.33 vs. 6.08, p = 0.039). Lipid profile analysis post-surgery showed an increase in total cholesterol (4.38 vs. 5.09 mmol/L, p < 0.001) and high-density lipoprotein (HDL) (0.88 vs. 1.52 mmol/L, p < 0.001), with a decrease in triglycerides (1.75 vs. 1.01 mmol/L, p = 0.007). FGF21 positively correlated with growth hormone (GH), p = 0.0015, r = 0.59, and with insulin like growth factor 1 (IGF-1), p = 0.03, r = 0.431. Conclusion FGF21 levels were increased following gastric sleeve surgery in obese male patients and were positively correlated with growth hormone and insulin IGF-1. These findings provide insights into the metabolic alterations following bariatric surgery and highlight the potential role of FGF21 as an important molecule in obesity management and treatment.

Study on the effect and mechanism of Yanghe decoction Huacai on tissue repair ofsyndrome after anal fistula surgery.

To observe the clinical efficacy and safety of Yanghe decoction Huacai for the repair of Yin syndrome wounds with slow-healing after anal fistula surgery. A total of 120 patients with slow-healing negative wounds with after low-grade anal fistula surgery who met the inclusion criteria were divided into a treatment group and a control group based on a random number table method, with 60 patients in the treatment group and 60 patients in the control group. The treatment group was given Yanghe decoction Huacai in combination with routine treatment; the control group was only given routine treatment, in which the wound surface was disinfected with iodine, and then covered with sterile gauze. The course of treatment in both groups was 10 d. After treatment, the wound secretion score, wound granulation tissue score, the expression levels of basic fibroblast growth factor (bFGF), transforming growth factor β1 (TGF-β1), and epidermal growth factor (EGF) in the wound, wound healing time and clinical efficacy were compared. There was no significant difference in age or gender between the two groups (P > 0.05). On the 10th and 15th days after the surgery, the wound secretion scores were higher in the treatment group than in the control group (P < 0.01). Comparing the two groups at the 10th and 15th day after surgery, the granulation tissue growth scores in the treatment group were better than the in control group (P < 0.01). On the 10th and 15th day after operation, the expression levels of bFGF, TGF-β1 and EGF factors in the treatment group were stronger than those in the control group. The healing time of the wounds in the treatment group was significantly shorter than in the control group (P < 0.01). The clinical efficacy of the two groups after treatment was compared, and the overall efficacy of the treatment group was significantly higher than that of the control group (P < 0.01). Yanghe decoction Huacai have significant efficacy in the treatment of slow-healing wounds with Yin syndrome after anal fistula surgery. It improves wound secretions, promotes the growth of wound granulation tissue, and shortens wound healing time. Its mechanism of action may be related to the control of wound inflammation. It is related to increasing the expression of bFGF, TGF-β1 and EGF in wound tissue, and promoting wound angiogenesis and fibroblast proliferation.

Causal effects of inflammatory cytokines on cardiovascular diseases: Insights from genetic evidence

BackgroundThe causal relationship between inflammatory cytokines and cardiovascular diseases (CVDs) has not been fully elucidated. Exploring this relationship between circulating inflammatory cytokines and CVDs is crucial for early clinical diagnosis and effective treatment. Methods and ResultsThis study investigated the causal relationships between 41 inflammatory cytokines and six CVDs: heart failure (HF), myocardial infarction (MI), unstable angina pectoris (UAP), stable angina pectoris (SAP), valvular heart disease (VHD), and aortic aneurysm (AA), using the Mendelian Randomization (MR) method. The primary analysis employed the inverse-variance weighted (IVW) method within MR. Heterogeneity and pleiotropy were assessed through MR-Egger regression and the Q statistic. Strong evidence supported the effect of macrophage inflammatory protein-1β (MIP-1β) on MI (OR = 1.062, P < 0.001, FDR <0.001). Suggestive evidence showed that the Beta nerve growth factor increased the risk of MI (OR = 1.145, P = 0.025), but the stem cell factor (SCF) demonstrated a potential protective effect against MI (OR = 0.910, P = 0.04). SCF and hepatocyte growth factor (HGF) exhibited potential protective effects against SAP. No inflammatory cytokine was associated with UAP. Monocyte chemotactic protein-1 was linked to an increased risk of VHD (OR = 1.056, P = 0.049). Higher levels of interleukin-13 (IL-13), interferon gamma-induced protein 10 (IP-10), and growth-regulated oncogene-alpha were associated with increased susceptibility to HF. Elevated basic fibroblast growth factor (bFGF) levels exhibited protective effects against AA (OR = 0.751, P = 0.038). Reverse MR analyses revealed that AA significantly decreased circulating TNF-related apoptosis-inducing ligand (TRAIL) levels (OR = 0.907, P < 0.001, FDR = 0.01). MI significantly increased circulating IL-12-p70 levels (OR = 1.146, P < 0.001, FDR = 0.014). Suggestive evidence indicated the Causal effects of six CVDs on 17 circulating inflammatory cytokines. ConclusionsThis study clarified the causal relationships between specific inflammatory cytokines and six CVDs, providing novel insights and evidence into the genetic involvement of inflammatory cytokines in CVDs. These inflammatory cytokines may be potential biomarkers for early disease diagnosis and treatment evaluation.

Cystinosis-associated metabolic bone disease across ages and CKD stages 1-5D/T.

The pathophysiology of cystinosis-associated metabolic bone disease is complex. We hypothesized a disturbed interaction between osteoblasts and osteoclasts. Binational cross-sectional multicenter study. Hospital clinics. One hundred and three patients with cystinosis (61% children) with chronic kidney disease (CKD) stages 1-5D/T. Ten key bone markers. Skeletal complications occurred in two-thirds of the patients, with adults having a five-fold increased risk compared to children. Patients with CKD stages 1-3 showed reduced z-scores for serum phosphate and calcium, suppressed fibroblast growth factor 23 (FGF23) and parathyroid hormone levels in conjunction with elevated bone-specific alkaline phosphatase levels. Serum phosphate was associated with estimated glomerular filtration rate, combined phosphate and active vitamin D treatment, and native vitamin D supplementation, while serum calcium was associated with age and dosage of active vitamin D. Sclerostin was generally elevated in children, and associated with age, FGF23 levels, and treatment with active vitamin D and growth hormone. The osteoclast marker tartrate-resistant acid phosphatase 5b was increased, and associated with age and treatment with active vitamin D. The ratio of soluble ligand of receptor activator of nuclear factor-κB (sRANKL) and osteoprotegerin (OPG), a surrogate for the regulation of osteoclastogenesis by osteoblasts, was decreased and associated with phosphate and 1,25(OH)2D3 levels. These changes were only partly corrected after transplantation. Bone health in cystinosis deteriorates with age, which is associated with increased osteoclast activity despite counterregulation of osteoblasts via OPG/RANKL, which in conjunction with elevated sclerostin levels and persistent rickets/osteomalacia may promote progressive bone loss.

Autosomal Recessive Hypophosphatemic Rickets Type 2 Associated with a Novel ENPP1 Variant in a Taiwanese Girl.

Autosomal recessive hypophosphatemic rickets (HR) type 2 (ARHR2) is a rare form of HR caused by variant of the gene encoding ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1). Our patient presented with a history of unsteady gait and progressively bowing legs that had commenced at the age of 1 year. Laboratory tests revealed an elevated level of fibroblast growth factor 23 (FGF23), hypophosphatemia, and a high urine phosphate level. Radiography revealed the typical features of rickets. Next-generation sequencing identified a previously reported c.783C>G (p.Tyr261Ter) and a novel c.1092-42A>G variant in the ENPP1 gene. The patient was prescribed oral phosphates and active vitamin D and underwent guided growth of both distal femora and proximal tibiae commencing at the age of 3 years. No evidence of generalized arterial calcification was apparent during follow-up, and growth rate was satisfactory.

Fibroblast growth factor 23 inhibition attenuates steroid-induced osteonecrosis of the femoral head through pyroptosis

Steroid-induced osteonecrosis of the femoral head (SONFH) is the predominant cause of non-traumatic osteonecrosis of the femoral head (ONFH). Impaired blood supply and reduced osteogenic activity of the femoral head are the key pathogenic mechanisms of SONFH. Fibroblast growth factor 23 (FGF23) levels are not only a biomarker for early vascular lesions caused by abnormal mineral metabolism, but can also act directly on the peripheral vascular system, leading to vascular pathology. The aim of this study was to observe the role of FGF23 on bone microarchitecture and vascular endothelium, and to investigate activation of pyroptosis in SONFH. Lipopolysaccharide (LPS) combined with methylprednisolone (MPS) was applied for SONFH mouse models, and adenovirus was used to increase or decrease the level of FGF23. Micro-CT and histopathological staining were used to observe the structure of the femoral head, and immunohistochemical staining was used to observe the vascular density. The cells were further cultured in vitro and placed in a hypoxic environment for 12 h to simulate the microenvironment of vascular injury during SONFH. The effect of FGF23 on osteogenic differentiation was evaluated using alkaline phosphatase staining, alizarin red S staining and expression of bone formation-related proteins. Matrigel tube formation assay in vitro and immunofluorescence were used to detect the ability of FGF23 to affect endothelial cell angiogenesis. Steroids activated the pyroptosis signaling pathway, promoted the secretion of inflammatory factors in SONFH models, led to vascular endothelial dysfunction and damaged the femoral head structure. In addition, FGF23 inhibited the HUVECs angiogenesis and BMSCs osteogenic differentiation. FGF23 silencing attenuated steroid-induced osteonecrosis of the femoral head by inhibiting the pyroptosis signaling pathway, and promoting osteogenic differentiation of BMSCs and angiogenesis of HUVECs in vitro.

Sodium sulphate ameliorates hypercholesterolemia via the upregulation of Cyp7a1 in hepatocytes and alleviates hepatic insulin resistance via the downregulation of Trib3 in mice with high cholesterol diets.

Amelioration of hypercholesterolemia is essential for the treatment of atherosclerotic cardiovascular disease. Sodium sulphate is the effective component of mirabilite, which has been used in traditional Chinese medicine for the treatment of various diseases. In the present study, C57BL/6 mice were fed with a high-cholesterol diet (HCD) for 7 weeks and were treated with sodium sulphate in the last three of those weeks. Sodium sulphate significantly reduced the total cholesterol level and the low-density lipoprotein cholesterol/high-density lipoprotein cholesterol ratio in the serum of mice fed the HCD. In addition, cytochrome P450 7a1 and 39a1 were significantly upregulated in the livers of mice treated with sodium sulphate. Furthermore, tribbles pseudokinase 3 expression was significantly increased in the livers of mice fed the HCD, but was significantly reduced by sodium sulphate treatment. In terms of the insulin signaling pathway, the ratio of phosphorylated AKT to total AKT in the livers of mice fed the HCD was significantly lower compared with that of control mice fed a normal diet, but was significantly increased by sodium sulphate treatment. Sodium sulphate treatment also reduced the levels of fibroblast growth factor (FGF)15 in the ileum and inhibited the FGF15/FGF receptor 4-Klotho β/c-Jun N-terminal kinase/c-Jun signaling pathway in the livers of mice fed the HCD. In addition, sodium sulphate changed the composition of the gut microbiota of mice fed the HCD. In conclusion, sodium sulphate may mitigate hypercholesterolemia and hepatic insulin resistance in mice fed an HCD.

Associations of Intact and C-Terminal FGF23 with Inflammatory Markers in Older Patients Affected by Advanced Chronic Kidney Disease.

Background: In patients with chronic kidney disease (CKD), Fibroblast Growth Factor 23 (FGF23) is markedly increased and has been proposed to interact with systemic inflammation. Methods: In this cross-sectional study, we evaluated the correlations of intact FGF23, c-terminal FGF23, and the FGF23 ratio (c-terminal to intact) with some inflammatory cytokines in 111 elderly patients with advanced CKD not yet in dialysis. Results: Estimated glomerular filtration rate (eGFR) was inversely correlated with intact FGF23 and c-terminal FGF23, as well as with interleukin 6 (IL-6), tumor necrosis factor alpha (TNFα), and monocyte chemoattractant protein-1 (MCP-1). Intact FGF23 levels were directly correlated with IL-6 (r = 0.403; p < 0.001) and TNFα (r = 0.401; p < 0.001) while c-terminal FGF23 was directly correlated with MCP-1 (r = 0.264; p = 0.005). The FGF23 ratio was, instead, inversely correlated with IL-6 (r = -0.326; p < 0.001). Multivariate analysis revealed that intact FGF23 was directly associated with TNFα [B = 0.012 (95% CI 0.006, 0.019); p = 0.003] and c-terminal FGF23 was directly associated with MCP-1 [B = 0.001 (95% CI 0.000, 0.002); p = 0.038], while the FGF23 ratio was inversely correlated with IL-6 [B = -0.028 (95% CI -0.047, -0.010); p = 0.002]. Conclusions: Our data demonstrate that, in CKD patients, intact FGF23 and the metabolites deriving from its proteolytic cleavage are differently associated with some inflammatory pathways. In particular, intact FGF23 is mainly associated with IL-6 and TNFα, c-terminal FGF23 with MCP-1, and the FGF23 ratio with IL6.

Estimated Proximal Tubule Fluid Phosphate Concentration and Renal Tubular Damage Biomarkers in Early Stages of Chronic Kidney Disease

IntroductionAn increase in proximal tubule fluid phosphate concentration is caused by increased serum fibroblast growth factor 23 (FGF23) levels, which resulted in renal tubular damage in a mouse model of chronic kidney disease (CKD). However, few human studies have supported this concept. This study aimed to explore the association among estimated proximal tubule fluid phosphate concentration (ePTFp), serum FGF23 levels, and renal tubular damage biomarkers in middle-aged and older populations with mild decline in renal function. MethodsThis cross-sectional study included 218 participants aged ≥45 with CKD stages G2–G4. Anthropometric measurements, blood tests, spot urine biomarkers, renal ultrasonography, cardiovascular assessment, smoking status, and medication usage were obtained in the morning in fasted states. The ePTFp was calculated using serum creatinine, urine phosphate, and creatinine concentrations. Urinary β2-microglobulin and liver-type fatty acid-binding protein (L-FABP) levels were evaluated to assess renal tubular damage.Results: ePTFp, serum FGF23, urinary β2-microglobulin, and urinary L-FABP levels increased with CKD stage progression (stages G2, G3, and G4). However, serum and urine phosphate concentrations were comparable across the CKD stages. Univariate analysis revealed a stronger correlation of ePTFp with serum FGF23, urinary β2-microglobulin, and urinary L-FABP levels than with the corresponding serum and urine phosphate concentrations. Multivariate analyses demonstrated that increased ePTFp was independently associated with elevated serum FGF23 and urinary β2-microglobulin levels, even after adjusting for potential covariates, including the estimated glomerular filtration rate and urinary albumin-to-creatinine ratio. ConclusionsOur results are consistent with the concept in mouse model and suggest that increased ePTFp are associated with increased serum FGF23 levels and renal tubular damage during the early stages of CKD.

The Effect of Periodontitis on Fibroblast Growth Factor 23 Levels in Predialysis Chronic Kidney Disease Patients.

Introduction Chronic kidney disease (CKD) is known to cause an increase in fibroblast growth factor 23 (FGF23). Periodontitis, a condition recognized as a risk factor for CKD, is also potentially associated with the increment of FGF23. This study aims to compare FGF23 levels in CKD patients with and without periodontitisand non-CKDpatients with and without periodontitis. Correlation with serum phosphate, calcium, and intact parathyroid hormone (iPTH) was assessed. Additionally, associations between FGF23, calcium, phosphate, iPTH, creatinine, urea, plaque score, and bleeding score with periodontitis in CKD patients were determined. Method A total of 124 participants were categorized into four groups: CKD patients with periodontitis (n=31), CKD patients without periodontitis (n=32), periodontitis patients without CKD (n=32), and healthy population (n=29). The selected CKD patients include those from stages 3 and 4 (predialysis) patients. Serum levels of FGF23, calcium, phosphate, iPTH, creatinine, and urea were analyzed. Oral examinations were conducted to determine the presence and absence of periodontitis and assess plaque and bleeding scores. Result A significantly higher level of FGF23 was found in CKD compared to non-CKD groups; however, no difference was observed with the presence of periodontitis in both CKD and non-CKD. There was no significant correlation found between FGF23 and serum calcium, phosphate, or iPTH concerning periodontal status. Apart from the bleeding score, there was no association between FGF23, calcium, phosphate, iPTH, creatinine, urea, and plaque score with the presence of periodontitis in CKD patients. Conclusion The presence of periodontitis was not associated with higher FGF23 levels in CKD patients. Changes in FGF23, calcium, phosphate, iPTH, creatinine, urea, and plaque score could not be attributed to the presence of periodontitis in CKD patients.

Fibroblast growth factor 23-mediated regulation of osteoporosis: Assessed via Mendelian randomization and invitro study.

Despite numerous investigations on the influence of fibroblast growth factor 23 (FGF23), α-Klotho and FGF receptor-1 (FGFR1) on osteoporosis (OP), there is no clear consensus. Mendelian randomization (MR) analysis was conducted on genome-wide association studies (GWASs)-based datasets to evaluate the causal relationship between FGF23, α-Klotho, FGFR1 and OP. The primary endpoint was the odds ratio (OR) of the inverse-variance weighted (IVW) approach. Furthermore, we stably transfected FGF23-mimic or siRNA-FGF23 into human bone marrow mesenchymal stem cells (hBMSCs) in culture and determined its cell proliferation and the effects on osteogenic differentiation. Using MR analysis, we demonstrated a strong correlation between serum FGF23 levels and Heel- and femoral neck-BMDs, with subsequent ORs of 0.919 (95% CI: 0.860-0.983, p = 0.014) and 0.751 (95% CI: 0.587-0.962; p = 0.023), respectively. The expression levels of FGF23 were significantly increased in femoral neck of patients with OP than in the control cohort (p < 0.0001). Based on our invitro investigation, after overexpression of FGF23, compared to the control group, the BMSC's proliferation ability decreased, the expression level of key osteogenic differentiation genes (RUNX2, OCN and OSX) significantly reduced, mineralized nodules and ALP activity significantly decreased. After silencing FGF23, it showed a completely opposite trend. Augmented FGF23 levels are causally associated with increased risk of OP. Similarly, FGF23 overexpression strongly inhibits the osteogenic differentiation of hBMSCs, thereby potentially aggravating the pathological process of OP.