Fibroblast Growth Factor 23 Levels Research Articles

A novel miR-466l-3p/FGF23 axis promotes osteogenic differentiation of human bone marrow mesenchymal stem cells

BackgroundMicroRNAs (miRNAs) regulate osteogenic differentiation processes and influence the development of osteoporosis (OP). This study aimed to investigate the potential role of miR-466 l-3p in OP. MethodsThe expression levels of miR-466 l-3p and fibroblast growth factor 23 (FGF23) were quantified in the trabeculae of the femoral neck of 40 individuals with or without OP using quantitative reverse transcription-polymerase chain reaction (qRT-PCR). The impact of miR-466 l-3p or FGF23 expression on cell proliferation and the expression levels of runt-related transcription factor 2 (RUNX2), type I collagen (Col1), osteocalcin (OCN), osterix (OSX) and dentin matrix protein 1 (DMP1) was quantified in human bone marrow mesenchymal stem cells (hBMSCs) overexpressing miR-466 l-3p. Furthermore, alkaline phosphatase (ALP) staining and alizarin red staining were performed to measure ALP activity and the levels of calcium deposition, respectively. In addition, bioinformatics analysis, luciferase reporter assays, and RNA pull-down assays were conducted to explore the molecular mechanisms underlying the effects of miR-466 l-3p and FGF23 in osteogenic differentiation of hBMSCs. ResultsThe expression levels of miR-466 l-3p were significantly lower in femoral neck trabeculae of patients with OP than in the control cohort, whereas FGF23 levels exhibited the opposite trend. Furthermore, miR-466 l-3p levels were upregulated and FGF23 levels were downregulated in hBMSCs during osteogenic differentiation. Moreover, the high miR-466 l-3p expression enhanced the mRNA expression of RUNX2, Col1, OCN, OSX and DMP1, as well as cell proliferation, ALP activity, and calcium deposition in hBMSCs. FGF23 was found to be a direct target of miR-466 l-3p. FGF23 overexpression downregulated the expression of osteoblast markers and inhibited the osteogenic differentiation induced by miR-466 l-3p overexpression. qRT-PCR and Western blot assays showed that miR-466 l-3p overexpression decreased the expression levels of mRNAs and proteins associated with the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling pathway, whereas FGF23 upregulation exhibited the opposite trend. ConclusionIn conclusion, these findings suggest that miR-466 l-3p enhances the osteogenic differentiation of hBMSCs by suppressing FGF23 expression, ultimately preventing OP.

Causal relationship between inflammatory proteins and glioblastoma: a two-sample bi‑directional mendelian randomization study.

Background: Observational studies have indicated a potential correlation between glioblastoma and circulating inflammatory proteins. Further investigation is required to establish a causal relationship between these two factors. Methods: We performed a Mendelian randomization (MR) analysis using genome-wide association study (GWAS) summary of 91 circulating inflammation-related proteins (N = 14,824) to assess their causal impact on glioblastoma. The GWAS summary data for glioblastoma included 243 cases and 287,137 controls. The inverse variance weighted (IVW) method was used as the primary analytical method to assess causality. Four additional MR methods [simple mode, MR-Egger, weighted median, and weighted mode] were used to supplement the IVW results. Furthermore, several sensitivity analyses were performed to assess heterogeneity, horizontal pleiotropy, and stability. Reverse MR analysis was also performed. glioblastoma transcriptomic data from The Cancer Genome Atlas (TCGA) were analyzed to validate the findings obtained through MR, while pathway and functional enrichment analyses were conducted to predict the potential underlying mechanisms. Results: Our findings from employing the inverse variance weighted method in our forward MR analysis provide robust evidence supporting a potential association between glioblastoma and elevated levels of Cystatin D, as well as decreased levels of fibroblast growth factor 21 (FGF21) in the circulation. Moreover, our reverse MR analysis revealed that glioblastoma may contribute to increased concentrations of C-X-C motif chemokine 9 (CXCL9) and Interleukin-33 (IL-33) in the bloodstream. Transcriptomic analysis showed that FGF21 expression was inversely associated with the risk of developing glioblastoma, whereas an increased risk was linked to elevated levels of CXCL9 and IL-33. Pathway and functional enrichment analyses suggested that Cystatin D might exert its effects on glioblastoma through intracellular protein transport, whereas FGF21 might affect glioblastoma via glucose response mechanisms. Conclusion: These results indicate that FGF21 is a significant factor in glioblastoma susceptibility. Glioblastoma also affects the expression of inflammatory proteins such as C-X-C motif chemokine 9 and Interleukin-33, providing new insights into the mechanisms of glioblastoma genesis and clinical research.

Hyperglycaemia perturbs blood-brain barrier integrity through its effects on endothelial cell characteristics and function

ABSTRACT Breakdown of blood-brain barrier (BBB) represents a key pathology in hyperglycemia-mediated cerebrovascular damage after an ischemic stroke. As changes in the level and nature of vasoactive agents released by endothelial cells (ECs) may contribute to BBB dysfunction, this study first explored the specific impact of hyperglycemia on EC characteristics and secretome. It then assessed whether secretome obtained from ECs subjected to normoglycaemia or hyperglycemia might regulate pericytic cytokine profile differently. Using a triple cell culture model of human BBB, composed of brain microvascular EC (BMEC), astrocytes and pericytes, this study showed that exposure to hyperglycemia (25 mM D-glucose) for 72 h impaired the BBB integrity and function as evidenced by decreases in transendothelial electrical resistance and increases in paracellular flux of sodium fluorescein. Dissolution of zonula occludens-1, a tight junction protein, and appearance of stress fibers appeared to play a key role in this pathology. Despite elevations in angiogenin, endothelin-1, interleukin-8 and basic fibroblast growth factor levels and a decrease in placental growth factor levels in BMEC subjected to hyperglycemia vs normoglycaemia (5.5 mM D-glucose), tubulogenic capacity of BMECs remained similar in both settings. Similarly, pericytes subjected to secretome obtained from hyperglycemic BMEC released higher quantities of macrophage migration inhibitory factor and serpin and lower quantities of monocyte chemoattractant protein-1, intercellular adhesion molecule, interleukin-6 and interleukin-8. Taken together these findings indicate the complexity of the mechanisms leading to BBB disruption in hyperglycemic settings and emphasize the importance of endothelial cell-pericyte axis in the development of novel therapeutic strategies.

Correlation of serum fibroblast growth factor-23 levels and calcium phosphate products levels in chronic kidney disease; sub analysis of chronic kidney disease-mineral and bone disorder study

<em data-sider-select-id="0e59b1fc-fce5-41b4-b987-316daa778de4">Introduction: The body produces fibroblast growth factor-23 (FGF-23) to maintain normal phosphate levels when hyperphosphatemia occurs. Production of FGF-23 indirectly causes hypocalcemia. Phosphate and calcium disturbances also occur in chronic kidney disease (CKD), therefore this adaptation mechanism applies. This situation; however, only manifests in the early stages of CKD; if the estimated glomerular filtration rate (eGFR) is less than 30% of normal. This adaptation is no longer adequate and levels of calcium-phosphate (Ca×P) products and FGF-23 still rise. <em data-sider-select-id="f0dc3bf1-1598-419e-9de6-fe837eadc8e6">Objectives: In this study, the correlation between both the serum levels of FGF-23 and Ca×P products in CKD was analyzed. <em data-sider-select-id="a367eeb1-7c32-4bf0-98ef-e6ae52522dc7">Patients and Methods: A cross-sectional study including 78 subjects with CKD stages 3 to 5 dialysis was conducted. Serum FGF-23 levels were determined using the enzyme-linked immunosorbent assay (ELISA) method and Ca×P product levels were calculated using the formula calcium (mg/ dL) × phosphate (mg/dL). The Kolmogorov-Smirnov test and Spearman’s test were conducted in the statistical study. If the P value is less than 0.05, the statistical findings are significant. <em data-sider-select-id="e286c166-6c09-432e-b832-c902b1a13b81">Results: Serum FGF-23 levels and Ca×P product levels were shown to be significantly correlated. This analysis of the two correlations was independent of age and diabetes mellitus (DM). Based on stages of CKD, serum FGF-23 levels and Ca×P product levels were discovered to be significantly correlated only at stage 5 of non-dialysis. <em data-sider-select-id="9b3534d4-deaa-4ccf-8b82-745bb5380661">Conclusion: Increasing serum FGF-23 levels were correlated with increased Ca×P product levels, particularly in CKD stage 5 non-dialysis subjects. This correlation was independent of age and DM.

Abstract 1084: Differential Expression Of MicroRNAs In Patients With End Stage Renal Disease Target The Klotho/FGF23 Signaling Axis And May Attenuate Left Ventricular Hypertrophy

Introduction: Conventional hemodialysis (CHD) is the standard method of dialysis with concomitant changes in the cardiovascular system that may result in left ventricular hypertrophy (LVH). Importantly, increased frequency of dialysis reduces cardiac complications by regulating fluid status. Klotho and Fibroblast Growth Factor 23 (FGF23) has been shown to be expressed in a reciprocal fashion in patients with end-stage renal disease with LVH. Research Questions/Hypothesis: The Klotho/FGF23 axis may be regulated by circulating microRNAs (miRs) in CHD patients that transition to nocturnal hemodialysis (NHD) thereby regulating the development of LV mass. Goals/ Aims: To define alterations in expression of circulating miRs in patients transitioning from CHD to NHD and correlate the miR signatures with alterations in LV mass. Methods/Approach: Total RNA was isolated from serum of patients undergoing CHD and NHD and used to define the differential expression of miRs via microarray analysis. In parallel, circulating levels of Klotho and FGF23 were measured via ELISA analysis. Results/Data: We identified miRs with differential expression patterns in CHD vs NHD that targeted the Klotho/FGF23 axis. In patients with ≥10% increase or decrease of LV mass, a subset of miRs were identified that regulated the Klotho/FGF23 axis, namely let-7 members, miR-200c, miR-1 and miR-30c. There was no significant correlation between Klotho levels and LV mass in ESRD patients (p >0.05). However, we observed an association between FGF23 levels and LV mass in patients who were treated with NHD such that there were increased circulating FGF23 levels with increased LV mass, and vice versa (p=0.008, two-way ANOVA). Conclusion: Our novel findings have identified the differential expression of miRs in patients that transition from CHD to NHD with concomitant alterations in LV mass. Therapeutic delivery of miR antagomirs or mimics may mitigate cardiac hypertrophy in patients with renal disease by regulating the Klotho/FGF23 axis.

Evaluation of serum levels of fibroblast growth factor-2 and carcinoembryonic antigen in patients with squamous cell carcinoma of the oral cavity

Evaluation of serum levels of fibroblast growth factor-2 and carcinoembryonic antigen in patients with squamous cell carcinoma of the oral cavity

Evaluation of serum levels of fibroblast growth factor-2 and carcinoembryonic antigen in patients with squamous cell carcinoma of the oral cavity

Evaluation of serum levels of fibroblast growth factor-2 and carcinoembryonic antigen in patients with squamous cell carcinoma of the oral cavity

An unusual cause of osteomalacia in a young lady

Abstract Oncogenic osteomalacia is a rare entity, caused by excessive secretion of fibroblast growth factor-23 (FGF-23) from the peripherally located benign tumours of mesenchymal origin. Patients usually present with chronic widespread pain and fatigue. Diagnostic approach involves demonstration of excessive urinary loss of phosphate and the high plasma level of FGF-23. Whole of PET-CT scan or whole body MRI scan are used to detect the tumour. PET/CT Ga-68 dotatate scan is required often when the other imaging modalities fail to detect the neoplasm. Here we present the case of a 32year old lady who presented to us with chronic low back pain and thorough evaluation helped us to diagnose this rare disease.

Relationship between fibroblast growth factor in plasma and carotid plaque neovascularization: a pilot study.

Unstable atherosclerotic carotid plaques with intraplaque neovascularization (IPN) carry a substantial risk for ischemic stroke. Conventional ultrasound methods fall short in detecting IPN, where superb microvascular imaging (SMI) has emerged as a promising tool for both visualizing and quantification. High levels of fibroblast growth factor 23 (FGF-23) have, in observational studies, been suggested as related to cardiovascular morbidity and mortality. The association of FGF-23 to atherosclerotic carotid plaque instability remains relatively unexplored. A cohort of twenty-nine patients with ≥50% atherosclerotic carotid stenosis underwent conventional carotid ultrasound, SMI, and blood tests, including measurement of FGF-23 in plasma. Nineteen patients were characterized as symptomatic and ten as asymptomatic. Our major findings were: i) Higher FGF-23 levels were strongly correlated with increased SMI-assessed IPN. ii) Neo-vessel count recorded by quantitative SMI was positively correlated to increased FGF-23 levels, but not with basic FGF levels. (iii) In contrast, traditional risk factors for plaque instability exhibited no noteworthy associations with SMI-assessed IPN or with FGF-23 levels. This pilot study suggest the potential of FGF-23 as a valuable marker for neovascularization and atherosclerotic carotid plaque instability as a risk factor for ischemic stroke. Further research involving larger cohorts and prospective data is necessary to understand FGF-23's role in this context comprehensively.

DNA methylation of skeletal muscle function-related secretary factors identifies FGF2 as a potential biomarker for sarcopenia.

Sarcopenia is characterized by progressive loss of muscle mass and function due to aging. DNA methylation has been identified to play important roles in the dysfunction of skeletal muscle. The aim of our present study was to explore the whole blood sample-based methylation changes of skeletal muscle function-related factors in patients with sarcopenia. The overall DNA methylation levels were analysed by using MethlTarget™ DNA Methylation Analysis platform in a discovery set consistent of 50 sarcopenic older adults (aged ≥65years) and 50 age- and sex-matched non-sarcopenic individuals. The candidate differentially methylated regions (DMRs) were further validated by Methylation-specific PCR (MSP) in another two independent larger sets and confirmed by pyrosequencing. Receiver operating characteristic (ROC) curve analysis was used to determine the optimum cut-off levels of fibroblast growth factor 2 (FGF2)_30 methylation best predicting sarcopenia and area under the ROC curve (AUC) was measured. The correlation between candidate DMRs and the risk of sarcopenia was investigated by univariate analysis and multivariate logistic regression analysis. Among 1149 cytosine-phosphate-guanine (CpG) sites of 27 skeletal muscle function-related secretary factors, 17 differentially methylated CpG sites and 7 differentially methylated regions (DMRs) were detected between patients with sarcopenia and control subjects in the discovery set. Further methylation-specific PCR identified that methylation of fibroblast growth factor 2 (FGF2)_30 was lower in patients with sarcopenia and the level was decreased as the severity of sarcopenia increased, which was confirmed by pyrosequencing. Correlation analysis demonstrated that the methylation level of FGF2_30 was positively correlated to ASMI (r=0.372, P<0.001), grip strength (r=0.334, P<0.001), and gait speed (r=0.411, P<0.001). ROC curve analysis indicated that the optimal cut-off value of FGF2_30 methylation level that predicted sarcopenia was 0.15 with a sensitivity of 84.6% and a specificity of 70.1% (AUC=0.807, 95% CI=0.756-0.858, P<0.001). Multivariate logistic regression analyses showed that lower FGF2_30 methylation level (<0.15) was significantly associated with increased risk of sarcopenia even after adjustment for potential confounders including age, sex, and BMI (adjusted OR=9.223, 95% CI: 6.614-12.861, P<0.001). Our results suggest that lower FGF2_30 methylation is correlated with the risk and severity of sarcopenia in the older adults, indicating that FGF2 methylation serve as a surrogate biomarker for the screening and evaluation of sarcopenia.

Relationships of serum FGF23 and α-klotho with atherosclerosis in patients with type 2 diabetes mellitus

BackgroundCompelling evidence suggests that calcium/phosphorus homeostasis-related parameters may be linked to diabetes mellitus and cardiovascular events. However, few studies have investigated the association of fibroblast growth factor 23 (FGF23), α-klotho and FGF23/α-klotho ratio with atherosclerosis in patients with type 2 diabetes mellitus (T2DM).ObjectiveThis study was designed to evaluate whether FGF23, α-klotho and FGF23/α-klotho ratio are associated with T2DM and further to explore the relationships between these three factors and atherosclerosis in Chinese patients with T2DM.MethodsSerum FGF23 and α-klotho levels were measured via an enzyme-linked immunosorbent assay (ELISA) kit, and the carotid intima-media thickness (CIMT) was assessed via high-resolution color Doppler ultrasonography. The associations of serum FGF23, α-klotho and FGF23/α-klotho ratio with atherosclerosis in T2DM patients were evaluated using multivariable logistic regression models.ResultsThis cross-sectional study involved 403 subjects (207 with T2DM and 196 without T2DM), 41.7% of the patients had atherosclerosis, and 67.2% of the carotid intima were thickened to a thickness greater than 0.9 mm. Compared with those in the lowest tertile, higher tertiles of FGF23 levels and FGF23/α-klotho ratio were positively associated with T2DM after adjusting for covariates, and serum α-klotho concentration was inversely correlated with T2DM (all P values < 0.01). Moreover, elevated serum FGF23 levels and FGF23/α-klotho ratio were positively associated with CIMT and carotid atherosclerosis in T2DM patients (all P values < 0.01). Further spline analysis similarly revealed linear dose‒response relationship (all P values < 0.01). And there was still significant differences in CIMT and carotid atherosclerosis between the highest group of α-klotho and the reference group in T2DM patients (P values = 0.05).ConclusionsT2DM was positively linearly related to serum FGF23 concentration and FGF23/α-klotho ratio, and negatively correlated with serum α-klotho concentration. Furthermore, both FGF23 and FGF23/α-klotho ratio were positively correlated with CIMT and atherosclerosis in T2DM patients, while α-klotho was inversely correlated with both CIMT and atherosclerosis, although the associations were not completely significant. Prospective exploration and potential mechanisms underlying these associations remain to be further elucidated.

Emerging concepts on the FGF23 regulation and activity.

Fibroblast growth factor 23 (FGF23) discovery has provided new insights into the regulation of Pi and Ca homeostasis. It is secreted by osteoblasts and osteocytes, and acts mainly in the kidney, parathyroid, heart, and bone. The aim of this review is to highlight the current knowledge on the factors modulating the synthesis of FGF23, the canonical and non-canonical signaling pathways of the hormone, the role of FGF23 in different pathophysiological conditions, and the anti-FGF23 therapy. This is a narrative review based on the search of PubMed database in the range of years 2000-2023 using the keywords local and systemic regulators of FGF23 synthesis, FGF23 receptors, canonical and non-canonical pathways, pathophysiological conditions and FGF23, and anti-FGF23 therapy, focusing the data on the molecular mechanisms. The regulation of FGF23 synthesis is complex and multifactorial. It is regulated by local factors and systemic regulators mainly involved in bone mineralization. The excessive FGF23 production is associated with different congenital diseases and with diseases occurring with a secondary high FGF23 production such as in chronic disease kidney and tumor-induced osteomalacia (TIO). The anti-FGF23 therapy appears to be useful to treat chromosome X-linked hypophosphatemia and TIO, but there are doubts about the handle of excessive FGF23 production in CKD. FGF23 biochemistry and pathophysiology are generating a plethora of knowledge to reduce FGF23 bioactivity at many levels that might be useful for future therapeutics of diseases associated with high-serum FGF23 levels.

The effects of burosumab on growth, nephrocalcinosis and cardiovascular outcomes in children with X-linked hypophosphatemia: a single-center experience

PurposeX-linked hypophosphatemia (XLH) is the most common cause of inherited rickets. It is characterized by chronic hypophosphatemia due to increased levels of Fibroblast Growth Factor 23 hormone (FGF23), renal phosphate wasting, and decreased renal vitamin D hydroxylation. Burosumab, an anti-FGF23 antibody, was approved in 2018 for XLH children.MethodsThis retrospective single-center study assessed the progression of clinical, biological, renal, and cardiovascular outcomes of XLH patients who started burosumab before 18 years of age, between July 2018 and June 2022.ResultsIn total, 12 children began burosumab treatment at a median age of 10.1(2.7–14.7) years, after 7.6 (1.1–11.3) years of conventional therapy. The last follow-up was 2.7(0.8–4.7) years after burosumab initiation, with 10 patients with at least 2 years of follow-up. Regarding the progression of anthropometric parameters, only height SDS significantly increased from baseline at the last follow-up. Regarding the biological parameters, as expected, at 12 months after starting burosumab and at the last follow-up, phosphate and alkaline phosphatase levels significantly improved. Although not significant, there was a trend towards an early increase of osteocalcin and crosslaps during the first months of therapy. Before starting burosumab, 5 patients (42%) had nephrocalcinosis (1 stage 1, 4 stage 2). One patient displayed a complete resolution of nephrocalcinosis after 1 year of treatment, and one patient showed improvement of nephrocalcinosis. No nephrocalcinosis appeared in a patient while being treated with burosumab. Cardiac ultrasounds remained normal in all.ConclusionOur real-life data confirm that burosumab improves outcomes in XLH children, including nephrocalcinosis and growth.

Morphological peculiarities of regeneration phases and dynamics of growth factor levels at using 2-ethyl-6-methyl-3-hydroxypyridinium n-acetyl-6-aminohexanoate for rat skin burns repairation

BACKGROUND: It was found that new derivatives of acexamic acid — N-acetyl-6-aminohexanoate of silver and 2-ethyl-6-methyl-3-hydroxypyridinium N-acetyl-6-aminohexanoate stimulate regeneration and mineralization of bone tissues in osteoporosis. However, to date, the effect of 2-ethyl-6-methyl-3-hydroxypyridinium N-acetyl-6-aminohexanoate on the features of reparative histogenesis and the relationship of its stages with the levels of growth factors in regenerating tissues during skin restoration after thermal burn has not been studied.&#x0D; AIM: To estimate the morphology dynamics of skin burn healing and its relationship with the levels of vascular endothelial growth factor and basic fibroblast growth factor growth factors in rat regenerating tissues to characterize the reparative properties of 2-ethyl-6-methyl-3-hydroxypyridinium N-acetyl-6-aminohexanoate.&#x0D; MATERIALS AND METHODS: 63 nonlinear rats were used to establish thermal burn wound model according to standard methodics. Burn wounds of the experimental group animals were treated with 2% ointment of 2-ethyl-6-methyl-3-hydroxypyridinium N-acetyl-6-aminohexanoate daily, control group 1 — the burns were not treated, control group 2 — ointment base was applied daily. Morphological examinations of regenerating tissues from the burn area were carried out on days 7, 14 and 21 of the experiment after standard sample preparation. The concentrations of growth factors in homogenates of regenerating tissues were determined by Enzyme Immunoassay.&#x0D; RESULTS: The inflammation phase is characterized by vascular endothelial growth factor active production and release from cells and morphologically accompanied by early neovasculogenesis in granulation tissue and significant differences in its thickness in rats of the experimental group. During the proliferation phase, activation of fibroblast reproduction and differentiation was associated with an increase in basic fibroblast growth factor levels and the maintenance of elevated vascular endothelial growth factor levels in all groups, especially high in experimental group rats. The epithelialization phase was accompanied by a statistically significant decrease in the content of basic fibroblast growth factor and vascular endothelial growth factor in regenerating skin tissues by 1.9 and 1.8 times, respectively, in comparison with the control groups.&#x0D; CONCLUSIONS: The obtained experimental data indicate 2% ointment with 2-ethyl-6-methyl-3-hydroxypyridinium N-acetyl-6-aminohexanoate has a reparative potential, as evidenced by the accelerated reduction both the area of burn defects and the average time for their healing in the experimental group compared to the control groups.

Gα11 deficiency increases fibroblast growth factor 23 levels in a mouse model of familial hypocalciuric hypercalcemia.

Fibroblast growth factor 23 (FGF23) production has recently been shown to increase downstream of Gαq/11-PKC signaling in osteocytes. Inactivating mutations in the gene encoding Gα11 (GNA11) cause familial hypocalciuric hypercalcemia (FHH) due to impaired calcium-sensing receptor signaling. We explored the effect of Gα11 deficiency on FGF23 production in mice with heterozygous (Gna11+/-) or homozygous (Gna11-/-) ablation of Gna11. Both Gna11+/- and Gna11-/- mice demonstrated hypercalcemia and mildly raised parathyroid hormone levels, consistent with FHH. Strikingly, these mice also displayed increased serum levels of total and intact FGF23 and hypophosphatemia. Gna11-/- mice showed augmented Fgf23 mRNA levels in the liver and heart, but not in bone or bone marrow, and also showed evidence of systemic inflammation with elevated serum IL-1β levels. Furin gene expression was significantly increased in the Gna11-/- liver, suggesting enhanced FGF23 cleavage despite the observed rise in circulating intact FGF23 levels. Gna11-/- mice had normal renal function and reduced serum levels of glycerol-3-phosphate, excluding kidney injury as the primary cause of elevated intact FGF23 levels. Thus, Gα11 ablation caused systemic inflammation and excess serum FGF23 in mice, suggesting that patients with FHH - at least those with GNA11 mutations - may be at risk for these complications.

High Fibroblast Growth Factor 23, Sialic Acids, and Albumin Modulation in Alzheimer’s Patients

Background: Alzheimer’s disease (AD) is a prevalent form of dementia, posing significant health and societal burdens. Pathologically characterized by neurofibrillary tangles and senile plaques, it lacks definitive diagnostic markers. Fibroblast growth factor (FGF)23 and Sialic Acids (Sias) are implicated in cell signaling and antioxidative defense, while lipid peroxidation (LPO) is linked to neurodegeneration. The aim of this study was to assess serum levels of Fibroblast Growth Factor 23 (FGF23), Malondialdehyde (MDA) as a marker of lipid peroxidation, Sialic Acids (Sias), and albumin in Alzheimer's disease (AD) patients compared to age-matched healthy controls. Method: A case-control study involving 17 AD patients and 17 healthy controls investigated serum levels of FGF23, Sias, malondialdehyde (MDA), and albumin. Biochemical assays and statistical analyses were conducted. Results: Biochemical analyses revealed a significant increase in serum FGF23 and MDA levels in AD patients compared to controls (p &lt; 0.05). Additionally, AD patients exhibited lower levels of serum Sias and albumin. Furthermore, in the patient group, serum MDA levels were inversely correlated with normalized global gray matter volume (GMV), adjusted for age, sex, and Child-Pugh class. Conclusion: This study underscores the potential of FGF23, MDA, Sias, and albumin as biomarkers for AD. Further research elucidating their roles in AD pathogenesis is warranted. Decreased FGF23 in AD may involve disrupted phosphate regulation and neuroprotection mechanisms. Elevated MDA suggests increased lipid peroxidation, contributing to neuronal damage. Reduced Sias may impair antioxidative defense, exacerbating oxidative stress. Low albumin levels correlate with cognitive decline and oxidative damage in AD.

A retrospective cohort of tumor-induced osteomalacia and case series of malignant disease.

We aimed to describe the clinical characteristics of a large cohort of patients diagnosed with tumor-induced osteomalacia (TIO), with a focus on patients with non-localizing and malignant TIO. This is a retrospective cohort of TIO patients in an academic medical center, diagnosed between January 1998 to May 2023. We described their demographics, biochemistries, tumor features, localization, treatment and complications. Of 68 patients diagnosed with TIO, 49 (72%) were localizing and 5 (7.4%) were malignant. Of 50 patients who attempted localizing procedures, 29 (58%) achieved cure. 20 (40%) had persistent disease due to wrong tumor targeted, or refractory or recurrent tumors, despite up to 6 procedural attempts. There was no difference in demographics, phosphorus or baseline fibroblast growth factor-23 (FGF23) levels between localizing versus non-localizing groups, and malignant versus non-malignant groups. Lower extremity was the commonest site of localization (37%), with 47% in bone and 53% in soft tissue. 60% of malignant cases were located in the trunk. Tumor size correlated with peak FGF23 (R=0.566, p<0.001) but was not associated with malignancy risk (p=0.479). A cut-off FGF23 of >20 times upper limit of normal in the presence of normal renal function (p=0.025), and recurrence after initial cure (p=0.013) were factors significantly associated with malignancy. The non-localizing group had lower survival than localizing group (p=0.0097). TIO is a condition with significant morbidity. Very high FGF23 level and disease recurrence are associated with malignant disease. Reasons behind the observation of higher mortality in non-localizing TIO should be further explored.

Fibroblast growth factor-23 and Alpha-Klotho concentrations in dogs with canine Leishmaniasis

This study aimed to assess the concentrations of Fibroblast Growth Factor-23 (FGF-23) and α-Klotho in healthy dogs and dogs at different stages of Canine Leishmaniasis (CanL), and investigate the changes of these parameters in relation to renal function and calcium‑phosphorus metabolism. A total of 74 dogs (22 healthy and 52 with CanL) of varying ages, sexes, and medium-sized breeds were included. Dogs with CanL were categorized into different stages (Stage I-IV) based on Leishvet recommendations. In addition to routine hematological parameters, plasma FGF-23, serum α-Klotho, urea, creatinine, phosphorus, calcium, parathormone, vitamin D concentrations, and urine protein/creatinine ratio were measured. Data from healthy dogs were compared to dogs with CanL overall and by stage. Dogs with CanL exhibited higher concentrations of FGF-23 (p < 0.05), α-Klotho, and parathormone (p < 0.001), as well as lower concentrations of vitamin D and calcium (p < 0.001). FGF-23 concentration was particularly elevated in Stage IV compared to other stages. However, no significant differences in α-Klotho levels were observed among the stages. FGF-23 levels showed a weak positive correlation with urea and creatinine concentrations and a moderate positive correlation with urine protein/creatinine ratio. This study demonstrated increased levels of FGF-23 and α-Klotho in dogs with CanL for the first time. The increase in FGF-23 levels was more prominent in advanced stages of the disease and correlated with higher urea and creatinine concentrations. These findings may serve as a basis for future diagnostic and therapeutic investigations, contributing to the understanding of the pathophysiology of kidney disease in CanL.

Human Fibroblast-Derived Matrix Hydrogel Accelerates Regenerative Wound Remodeling Through the Interactions with Macrophages.

Herein, a novel extracellular matrix (ECM) hydrogel is proposed fabricated solely from decellularized, human fibroblast-derived matrix (FDM) toward advanced wound healing. This FDM-gel is physically very stable and viscoelastic, while preserving the natural ECM diversity and various bioactive factors. Subcutaneously transplanted FDM-gel provided a permissive environment for innate immune cells infiltration. Compared to collagen hydrogel, excellent wound healing indications of FDM-gel treated in the full-thickness wounds are noticed, particularly hair follicle formation via highly upregulated β-catenin. Sequential analysis of the regenerated wound tissues disclosed that FDM-gel significantly alleviated pro-inflammatory cytokine and promoted M2-like macrophages, along with significantly elevated vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) level. A mechanistic study demonstrated that macrophages-FDM interactions through cell surface integrins α5β1 and α1β1 resulted in significant production of VEGF and bFGF, increased Akt phosphorylation, and upregulated matrix metalloproteinase-9 activity. Interestingly, blocking such interactions using specific inhibitors (ATN161 for α5β1 and obtustatin for α1β1) negatively affected those pro-healing growth factors secretion. Macrophages depletion animal model significantly attenuated the healing effect of FDM-gel. This study demonstrates that the FDM-gel is an excellent immunomodulatory material that is permissive for host cells infiltration, resorbable with time, and interactive with macrophages, where it thus enables regenerative matrix remodeling toward a complete wound healing.

FGF2 gene's antisense protein, NUDT6, plays a depressogenic role by promoting inflammation and suppressing neurogenesis without altering FGF2 signalling.

Fibroblast growth factor-2 (FGF2) is involved in the regulation of affective behaviour and shows antidepressant effects through the Akt and extracellular signal regulated kinase (ERK) 1/2 pathways. Nudix hydrolase 6 (NUDT6) protein is encoded from FGF2 gene's antisense strand and its role in the regulation of affective behaviour is unknown. Here, we overexpressed NUDT6 in the hippocampus and investigated its behavioural effects and the underlying molecular mechanisms affecting the behaviour. We showed that increasing hippocampal NUDT6 results in depression-like behaviour in rats without changing FGF2 levels or activating its downstream effectors, Akt and ERK1/2. Instead, NUDT6 acted by inducing inflammatory signalling, specifically by increasing S100 calcium binding protein A9 (S100A9) levels, activating nuclear factor-kappa B-p65 (NF-κB-p65), and elevating microglia numbers along with a reduction in neurogenesis. Our results suggest that NUDT6 could play a role in major depression by inducing a proinflammatory state. This is the first report of an antisense protein acting through a different mechanism of action than regulationof its sense protein. The opposite effects of NUDT6 and FGF2 on depression-like behaviour may serve as a mechanism to fine-tune affective behaviour. Our findings open up new venues for studying the differential regulation and functional interactions of sense and antisense proteins in neural function and behaviour, as well as in neuropsychiatric disorders. KEY POINTS: Hippocampal overexpression of nudix hydrolase 6 (NUDT6), the antisense protein of fibroblast growth factor-2 (FGF2), increases depression-like behaviour in rats. Hippocampal NUDT6 overexpression triggers a neuroinflammatory cascade by increasing S100 calcium binding proteinA9 (S100A9) expression and nuclear NF-κB-p65 translocation in neurons, in addition to microglial recruitment and activation. Hippocampal NUDT6 overexpression suppresses neurogenesis. NUDT6 exerts its actions without altering the levels or downstream signalling pathways of FGF2.