Significance of serum fibroblast growth factor-23 and miR-208b in pathogenesis of atrial fibrillation and their relationship with prognosis

BACKGROUND The incidence and prevalence of atrial fibrillation are increasing each year,and this condition is one of the most common clinical arrhythmias.AIM To investigate the levels and significance of serum fibroblast growth factor 23(FGF-23)and miR-208 b in patients with atrial fibrillation and their relationship with prognosis.METHODS From May 2018 to October 2019,240 patients with atrial fibrillation were selected as an observation group,including 134 with paroxysmal atrial fibrillation and 106 with persistent atrial fibrillation;150 patients with healthy sinus rhythm were selected as a control group.The serum levels of FGF-23 and miR-208 b in the two groups were measured.In the observation group,cardiac parameters were determined by echocardiography.RESULTS The serum levels of FGF-23 and miR-208 b in the observation group were 210.20±89.60 ng/mL and 5.30±1.22 ng/mL,which were significantly higher than the corresponding values in the control group(P<0.05).In the observation group,the serum levels of FGF-23 and miR-208 b in patients with persistent atrial fibrillation were 234.22±70.05 ng/mL and 5.83±1.00 ng/mL,which were significantly higher than the corresponding values in patients with paroxysmal atrial fibrillation(P<0.05).The left atrial dimension(LAD)of patients with persistent atrial fibrillation was 38.81±5.11 mm,which was significantly higher than that of patients with paroxysmal atrial fibrillation(P>0.05).The serum levels of FGF-23and miR-208 b were positively correlated with the LAD(r=0.411 and 0.382,P<0.05).In the observation group,the serum levels of FGF-23 and miR-208 b in patients with a major cardiovascular event(MACE)were 243.30±72.29 ng/mL and 6.12±1.12 ng/mL,which were significantly higher than the corresponding values in patients without a MACE(P<0.05).CONCLUSION The serum levels of FGF-23 and miR-208 b are increased in patients with atrial fibrillation and are related to the type of disease,cardiac parameters,and prognosis.

The hypoxia-inducible factor-1α activates ectopic production of fibroblast growth factor 23 in tumor-induced osteomalacia

Tumor-induced osteomalacia （TIO） is a rare paraneoplastic syndrome in which ectopic production of fibroblast growth factor 23 （FGF23） by non-malignant mesenchymal tumors causes phosphate wasting and bone fractures. Recent studies have implicated the hypoxia-inducible factor-la （HIF-la） in other phosphate wasting disorders caused by elevated FGF23, including X-linked hypophosphatemic rickets and autosomal dominant hypophosphatemia. Here we provide evidence that HIF-la mediates aberrant FGF23 in TIO by transcriptionally activating its promoter. Immunohistochemical studies in phosphaturic mesenchymal tumors resected from patients with documented TIO showed that HIF-la and FGF23 were co-localized in spindle- shaped cells adjacent to blood vessels. Cultured tumor tissue produced high levels of intact FGF23 and demonstrated increased expression of HIF-la protein. Transfection of MC3T3-E1 and Saos-2 cells with a HIF-la expression construct induced the activity of a FGF23 reporter construct. Prior treatment of tumor organ cultures with HIF-la inhibitors decreased HIF-la and FGF23 protein accumulation and inhibited HIF-la-induced luciferase reporter activity in transfected cells. Chromatin immunoprecipitation assays confirmed binding to a HIF-la consensus sequence within the proximal FGF23 promoter, which was eliminated by treatment with a HIF-la inhibitor. These results show for the first time that HIF-la is a direct transcriptional activator of FGF23 and suggest that upregulation of HIF-la activity in TIO contributes to the aberrant FGF23 production in these patients.

Tumor-induced osteomalacia with elevated fibroblast growth factor 23: a case of phosphaturic mesenchymal tumor mixed with connective tissue variants and review of the literature

Tumor-induced osteomalacia (TIO), or oncogenic osteomalacia (OOM), is a rare acquired paraneoplastic disease characterized by renal phosphate wasting and hypophosphatemia. Recent evidence shows that tumor-overexpressed fibroblast growth factor 23 (FGF23) is responsible for the hypophosphatemia and osteomalacia. The tumors associated with TIO are usually phosphaturic mesenchymal tumor mixed connective tissue variants (PMTMCT). Surgical removal of the responsible tumors is clinically essential for the treatment of TIO. However, identifying the responsible tumors is often difficult. Here, we report a case of a TIO patient with elevated serum FGF23 levels suffering from bone pain and hypophosphatemia for more than three years. A tumor was finally located in first metacarpal bone by octreotide scintigraphy and she was cured by surgery. After complete excision of the tumor, serum FGF23 levels rapidly decreased, dropping to 54.7% of the preoperative level one hour after surgery and eventually to a little below normal. The patient's serum phosphate level rapidly improved and returned to normal level in four days. Accordingly, her clinical symptoms were greatly improved within one month after surgery. There was no sign of tumor recurrence during an 18-month period of follow-up. According to pathology, the tumor was originally diagnosed as "glomangioma" based upon a biopsy sample, "proliferative giant cell tumor of tendon sheath" based upon sections of tumor, and finally diagnosed as PMTMCT by consultation one year after surgery. In conclusion, although an extremely rare disease, clinicians and pathologists should be aware of the existence of TIO and PMTMCT, respectively.

Fibroblast growth factor 23 and bone mineralisation

Fibroblast growth factor 23 （FGF23） is a hormone that is mainly secreted by osteocytes and osteoblasts in bone. The critical role of FGF23 in mineral ion homeostasis was first identified in human genetic and acquired rachitic diseases and has been further characterised in animal models. Recent studies have revealed that the levels of FGF23 increase significantly at the very early stages of chronic kidney disease （CKD） and may play a critical role in mineral ion disorders and bone metabolism in these patients. Our recent publications have also shown that FGF23 and its cofactor, Klotho, may play an independent role in directly regulating bone mineralisation instead of producing a systematic effect. In this review, we will discuss the new role of FGF23 in bone mineralisation and the pathophysiology of CKD-related bone disorders.

Significant roles of anti-aging protein klotho and fibroblast growth factor23 in cardiovascular disease

The klotho gene has been identified as an aging suppressor that encodes a protein involved in cardiovascular disease （CVD）. The inac- tivation of the klotho gene causes serious systemic disorders resembling human aging, such as atherosderosis, diffuse vascular calcification and shortened life span. Klotho has been demonstrated to ameliorate vascular endothelial dysfunction and delay vascular calcification. Fur- thermore, klotho gene polymorphisms in the human are associated with various cardiovascular events. Recent experiments show that klotho may reduce transient receptor potential canonical6 （TRPC6） channels, resulting in protecting the heart from hypertrophy and systolic dys- function. Fibroblast growth factor23 （FGF23） is a bone-derived hormone that plays an important role in the regulation of phosphate and vi- tamin D metabolism. FGF23 accelerates urinary phosphate excretion and suppresses 1,25-dihydroxy vitaminD3 （1,25（OH）2D3）synthesis in the presence ofFGF receptorl （FGFR1） and its co-receptor ldotho, principally in the kidney. The hormonal affects of circulating klotho pro- tein and FGF23 on vascular and heart have contributed to an understanding of their roles in the pathophysiology of arterial stiffness and left ventricular hypertrophy. Klotho and FGF23 appear to play a critical role in the pathogenesis of vascular disease, and may represent a novel potential therapeutic strategy for clinical intervention.

Distribution and localization of fibroblast growth factor-8 in rat brain and nerve cells during neural stem/progenitor cell differentiation

The present study explored the distribution and localization of fibroblast growth factor-8 and its potential receptor, fibroblast growth factor receptor-3, in adult rat brain in vivo and in nerve cells during differentiation of neural stem/progenitor cells in vitro. Immunohistochemistry was used to examine the distribution of fibroblast growth factor-8 in adult rat brain in vivo. Localization of fibroblast growth factor-8 and fibroblast growth factor receptor-3 in cells during neural stem/progenitor cell differentiation in vitro was detected by immunofluorescence. Flow cytometry and immunofluorescence were used to evaluate the effect of an anti-fibroblast growth factor-8 antibody on neural stem/progenitor cell differentiation and expansion in vitro. Results from this study confirmed that fibroblast growth factor-8 was mainly distributed in adult midbrain, namely the substantia nigra, compact part, dorsal tier, substantia nigra and reticular part, but was not detected in the forebrain comprising the caudate putamen and striatum. Unusual results were obtained in retrosplenial locations of adult rat brain. We found that fibroblast growth factor-8 and fibroblast growth factor receptor-3 were distributed on the cell membrane and in the cytoplasm of nerve cells using immunohistochemistry and immunofluorescence analyses. We considered that the distribution of fibroblast growth factor-8 and fibroblast growth factor receptor-3 in neural cells corresponded to the characteristics of fibroblast growth factor-8, a secretory factor. Addition of an anti-fibroblast growth factor-8 antibody to cultures significantly affected the rate of expansion and differentiation of neural stem/progenitor cells. In contrast, addition of recombinant fibroblast growth factor-8 to differentiation medium promoted neural stem/progenitor cell differentiation and increased the final yields of dopaminergic neurons and total neurons. Our study may help delineate the important roles of fibroblast growth factor-8 in brain activities and neural stem/progenitor cell differentiation.

Local inhibition of matrix metalloproteinases reduced M2 macrophage activity and impeded recovery in spinal cord transected rats after treatment with fibroblast growth factor-1 and nerve grafts

Alternatively activated macrophages （M2 macrophages） promote central nervous system regeneration. Our previous study demonstrated that treatment with peripheral nerve grafts and fibroblast growth factor-1 recruited more M2 macrophages and improved partial functional recovery in spinal cord transected rats. The migration of macrophages is matrix metalloproteinase （MMP） dependent. We used a general inhibitor of MMPs to influence macrophage migration, and we examined the migration of macrophage populations and changes in spinal function. Rat spinal cords were completely transected at Ts, and 5 mm of spinal cord was removed （group T）. In group R, spinal cord-transected rats received treatment with fibroblast grow th factor- 1 and peripheral nerve grafts. In group RG, rats received the same treatment as group R with the addition of 200 μM GM6001 （an MMP inhibitor） to the fibrin mix. We found that MMP-9, but not MMP- 2, was upregulated in the graft area of rats in group R. Local application of the MMP inhibitor resulted in a reduction in the ratio of arginase-1 （M2 macrophage subset）/inducible nitric oxide synthase-postive cells. When the MMP inhibitor was applied at 8 weeks postoperation, the partial functional recovery observed in group R was lost. This effect was accompanied by a decrease in brain-derived neurotrophic factor levels in the nerve graft. These results suggested that the arginase-1 positive population in spinal cord transected rats is a migratory cell population rather than the phenotypic conversion of early iNOS^＋ cells and that the migration of the arginase-1^＋ population could be regulated locally. Simultaneous application of MMP in- hibitors or promotion of MMP activity for spinal cord injury needs to be considered if the coadministered treatment involves M2 recruitment.

Expression of fibroblast growth factor-2 and fibroblast growth factor receptor-1 protein in the hippocampus in rats exhibiting chronic stress-induced depression

There is evidence that the expression of members of the fibroblast growth factor （FGF） protein family is altered in post-mortem brains of humans suffering from major depressive disorder. The present study examined whether the expression of fibroblast growth factor-2 （FGF2） and fibroblast growth factor receptor-1 （FGFR1） protein is altered following chronic stress in an animal model. Rats were exposed to 35 days of chronic unpredictable mild stress, and then tested using open-field and sucrose consumption tests. Compared with the control group, rats in the chronic stress group exhibited obvious depressive-like behaviors, including anhedonia, anxiety and decreased mobility. The results of western blot analysis and immunohistochemical analysis revealed a downregulation of the expression of FGF2 and FGFR1 in the hippocampus of rats, particularly in the CA1, CA3 and dentate gyrus. This decreased expression is in accord with the results of post-mortem studies in humans with major depressive disorder. These findings suggest that FGF2 and FGFR1 proteins participate in the pathophysiology of depressive-like behavior, and may play an important role in the mechanism of chronic stress-induced depression.

Fibroblast Growth Factor 23 and Left Ventricular Hypertrophy in Hemodialysis Patients

Background: Left ventricular hypertrophy (LVH) is a common cardiovascular complication and an independent risk factor for cardiovascular death in hemodialysis (HD) patients. Previous studies have shown that fibroblast growth factor 23 (FGF23), which has an important role in phosphate metabolism, is elevated in HD patients. Objectives: The aim of this study was to determine the association of FGF23 and LVH and the prognostic value of serum FGF23 level in HD patients. One hundred seven HD patients were evaluated for LVH by echocardiography. Serum FGF23 levels were measured using a commercial enzyme-linked immunosorbent assay kit. Results: Patients with LVH were more likely to have higher systolic blood pressure (BP) and LVH was significantly associated with female gender and higher serum levels of phosphate and calcium ×phosphate products. LVH was also associated with higher serum FGF23 level. Multivariate analysis indicated that serum FGF23 level, systolic BP, and serum phosphate level remained correlated with LVH. This suggested that serum FGF23 level is independently associated with LVH in our HD patients. Cox analysis indicated no significant difference in risk of death for patients with elevated serum FGF23 level. Conclusion: LVH has a high prevalence in HD patients, and FGF23 is independently associated with LVH but is not a predictor for prognosis during a 4-year follow-up period.

TRANSFORMING GROWTH FACTOR-β AND FIBROBLAST GROWTH FACTOR INDUCE LENS EPITHELIAL EXPLANT METAPLASIA:IMPLICATIONS FOR THE FORMATION OF SUBCAPSULAR OPACIFICATION

Objective. This study was to investigate the effects of transforming growth factor-β(TGFβ) and fi- broblast growth factor (FGF) in the subcapsular opacification formation of the lens. Methods. Lens epithelial explants from 10-day-old rats were cultured with TGFβ1 or TGFβ2 in the presence of FGF for 5 days, then were examined by light and electron microscopy, and by immunolocal- ization of smooth muscle(α-sm) actin and type I collagen. Results. In TGFβ/FGF-treated explants,extensive proliferation occured, with formation of spindle and star-shaped cells. These cells showed ultrastructure and biochemical features of fibroblast or myofibroblast. Prominent Golgi apparatus and rough endoplaic reticulum were observed in some cells. Intracellular micro- filaments with cytoplasmic dense babies and membrane associated dense bodies, features of smooth muscle cells, were also observed. Some cells showed reactivity to -sin actin antibody. TGFβ/FGF-treated ex- plants were strongly stained with type I collagen antibody. Condusion. In the presence of FGF, TGFβ1 and TGFβ2 induced lens epithelial cell (LEC ) proliferation and transformation into fibroblast or myofibroblast-like cells, with producing of abundant collagen matrix in the explants. The changes are similar to the metaplasia that occurrs in subcapsular opacification of the lens. The findings suggest that TGFβ and FGF plays a role in the pathogenesis of subcapsular opacification of the lens.

RNA interference affects tumorigenicity and expression of insulin-like growth factor-1,insulin-like growth factor-1 receptor,and basic fibroblast growth factor-2 in rat C6 glioma cells

BACKGROUND： Human gliomas are more likely to express basic fibroblast growth factor-2 （FGF-2） insulin-like growth factor-1（IGF-1）, and IGF-1 receptor （IGF-1R） than normal brain tissue. These factors activate signal transduction systems of Ras/MAPK and PI3K/Akl, which promote glioma growth. OBJECTIVE： To utilize RNA interference （RNAi） technique to down-regulate FGF-2, IGF-1, and IGF-1R gene expression, and to investigate the effects of these genes on rat C6 glioma cells, as well as the feasibility of RNAi for treating glioma. DESIGN, TIME AND SETTING： This neurooncological, randomized, controlled, in vivo and in vitro experiment, which used RNAi methodology, was performed at the Laboratory of Molecular Biology, Institute of Biochemistry, Chinese Academy of Sciences between August 2005 and February 2008. MATERIALS： Rat C6 cell lines were purchased from Shanghai Institute of Cellular Biology Affiliated to Chinese Academy of Sciences. Small interfering RNA （siRNA） was synthesized by Shanghai GenePharma. Anti-IGF-1, anti-IGF-1R, anti-FGF-2, anti-mouse and anti-rabbit IgG G1-HRP antibodies were provided by Santa Cruz Biotechnology, USA. Four to six week-old BALB/c nude mice were purchased from the Laboratory Animal Center, Chinese Academy of Sciences. METHODS： C6 glioma cells were transfected with siRNA, which was chemically synthesized in vitro to correspond to endogenous FGF-2, IGF-1, and IGF-1R genes. The inhibition ratio of targeting mRNA expression was detected by semiquantitative RT-PCR, and protein expression was determined by Western blot analysis. C6 glioma cell proliferation was observed using a growth curve C6 glioma cell apoptosis rate and cell cycle were detected by flow cytometry. C6 glioma cell growth regression was observed by transwell migration assay. In addition, nude mouse subcutaneous tumor models were used in this study. For studying the anti-tumor effects of IGF-1 and IGF-1R siRNA, two blank control groups, with six mice each, were set up： A （2.5 μg siRNA was injected one week after C6 cells were inoculated, Le., when tumor volume reached 8 mm × 8 mm） and B （siRNA was injected at the same time with C6 cells were inoculated. To study the effects of FGF-2 siRNA, the groups consisted of a blank control group, negative control group, 2.6 μg siRNA group, 4 μg siRNA group, and 5.3 μg siRNA group, with six mice each. MAIN OUTCOME MEASURES： mRNA and protein inhibition ratio of FGF-2, IGF-1, and IGF-1 R; C6 glioma cell proliferation, apoptosis, and cycle growth arrest; C6 glioma cell growth regression and subcutaneous tumorigenicity rates. RESULTS： All siRNA constructs proved to be effective. After 48 hours, transfection of 200 nmol/L siRNA resulted in a FGF-2 or IGF-1R gene inhibition ratio 〉 80% and an IGF-1 gene inhibition ratio of approximately 70%. Protein expression levels for FGF-2, IGF-1, and IGF-1R decreased in a dose-dependent manner following siRNA transfection, with an inhibition rate 〉 85%, 60%, and 50%, respectively. C6 glioma cell proliferation and apoptosis rates increased in proportion to siRNA. The apoptosis rate of C6 glioma cells induced by FGF-2, IGF-1, and IGF-1R siRNA was 39.96%, 15.07% and 22.47%, respectively （P 〈 0.01）. Transfection of 200 nmol/L IGF or IGF-1R siRNA for 48 hours suppressed C6 glioma cell migration. At 30 days after intratumoral injection of 2.6, 4, and 5.3 tJg FGF-2 siRNA, tumor growth regression rate of FGF-2 siRNA was 56%, 67%, and 86%, respectively. The tumor growth regression rate was 71.88% and 45.71%, respectively, when IGF-1 or IGF-1R siRNA was intratumorally injected 1 week after C6 glioma cell transplantation. When IGF-1 or IGF-1 R siRNA was intratumorally injected during C6 glioma cell transplantation, the tumor growth regression rate was 78.13% and 74.29%, respectively. CONCLUSION： siRNA transfection downregulated gene expression of FGF-2, IGF-1, and IGF-1R In addition, siRNA treatment markedly suppressed glioma cell proliferation, growth, and migration, and concomitantly reduced subcutaneous tumorigenicity.

血清脂联素、成纤维生长因子-23在心脏瓣膜置换术患者预后中的评估价值

目的探讨血清脂联素、成纤维生长因子-23(FGF23)水平在心脏瓣膜置换术患者预后中的评估价值。方法选取行心脏瓣膜置换术的患者98例为研究组。根据研究组患者的预后情况分为预后良好组(n=67)和预后不良组(n=31)。选取同期健康体检者90例为对照组。采用Spearman法分析血清脂联素、FGF23水平分别与血浆N末端B型利钠肽前体(NT-proBNP)水平和急性生理学与慢性健康状况评分系统Ⅱ(APACHEⅡ)评分的相关性。采用多因素Logistic回归分析法分析心脏瓣膜置换术患者预后的影响因素。绘制受试者工作特征(ROC)曲线分析血清脂联素、FGF23水平对心脏瓣膜置换术患者预后的预测价值。结果研究组血清FGF23、NT-proBNP水平、APACHEⅡ评分高于对照组,血清脂联素水平低于对照组,差异有统计学意义(P<0.05)。预后不良组血清FGF23、NT-proBNP水平和APACHEⅡ评分高于预后良好组,血清脂联素水平低于预后良好组,差异有统计学意义(P<0.05)。患者的血清FGF23水平与NT-proBNP水平、APACHEⅡ评分呈正相关(P<0.05)。血清脂联素水平与NT-proBNP水平、APACHEⅡ评分呈负相关(P<0.05)。血清脂联素、FGF23、NT-proBNP水平和APACHEⅡ评分为心脏瓣膜置换术患者预后的影响因素(P<0.05)。血清脂联素、FGF23单独预测和联合预测心脏瓣膜置换术患者预后的曲线下面积(AUC)分别为0.862、0.807、0.911。脂联素、FGF23联合预测的AUC大于单独预测,差异有统计学意义(P<0.05)。结论血清脂联素、FGF23联合预测心脏瓣膜置换术患者预后的效果较好。血清脂联素、FGF23有望成为评估心脏瓣膜置换术患者预后效果的有效指标。

外周血Lp-PLA2和FGF23水平变化与脑梗死后认知功能障碍的相关性

目的分析外周血脂蛋白相关磷脂酶A2(Lp-PLA2)、成纤维细胞生长因子23(FGF23)水平变化与脑梗死后患者认知功能障碍的相关性。方法选取2019-04—2022-12邯郸市中心医院收治的160例脑梗死患者为研究对象,根据患者是否发生认知功能障碍分为认知障碍组和非认知障碍组,对比2组基线资料及外周血Lp-PLA2、FGF23水平,并采用Logistic回归分析患者发生认知功能障碍的影响因素,采用Pearson相关性分析外周血Lp-PLA2、FGF23与简易智力状态评价量表(MMSE)评分的关系,采用ROC曲线评估外周血Lp-PLA2、FGF23对脑梗死后患者认知功能障碍的预测价值。结果160例脑梗死患者中,48例(30.00%)发生认知功能障碍。认知障碍组患者的平均年龄、高血压、糖尿病、吸烟、文化程度、MMSE评分及血清Lp-PLA2、FGF23水平等方面与非认知障碍组相比,差异有统计学意义(P<0.05)。Logistic回归分析显示,年龄、高血压、糖尿病、吸烟、文化程度低及血清Lp-PLA2、FGF23水平升高是影响脑梗死后认知功能障碍发生的独立危险因素(P<0.05)。Pearson相关性分析显示,脑梗死患者血清Lp-PLA2、FGF23水平与MMSE评分呈负相关(P<0.05)。ROC曲线显示,Lp-PLA2的曲线下面积为0.770,FGF23的曲线下面积为0.779,联合检测的曲线下面积为0.873(P<0.05),表示两者联合检测可作为评价脑梗死后认知功能障碍的有效指标。结论Lp-PLA2、FGF23在脑梗死后认知功能障碍患者血清中均呈高表达,二者联合检测有助于提高对脑梗死后认知功能障碍的预测价值。

血清维生素D结合蛋白、FGF23、Klotho与乳腺癌骨转移的相关性分析

目的骨转移是乳腺癌常见的并发症之一,严重影响患者的生存和预后。本研究旨在探究血清维生素D结合蛋白(vitamin D⁃binding protein,VDBP)、成纤维细胞生长因子23(fibroblast growth factor 23,FGF23)和Klotho蛋白在乳腺癌骨转移中的表达及临床意义。方法收集95例来自本院2019⁃08⁃01至2021⁃08⁃01的女性乳腺癌患者作为研究对象,经影像学和组织病理学方式诊断是否发生骨转移,将患者分为骨转移组36例,非骨转移组59例。分析两组患者的临床病理特征;采集患者外周血样本,通过ELISA对血清中VDBP、FGF23和Klotho进行定量分析;使用Spearman相关分析进行指标间的关联性分析;Logistic回归分析乳腺癌发生骨转移的影响因素;ROC曲线分析血清VDBP、FGF23和Klotho水平预测乳腺癌发生骨转移的价值。结果骨转移和非骨转移乳腺癌病理分级比较有统计学意义(P<0.05)。骨转移和非骨转移乳腺癌患者血清中VDBP、FGF23及Klotho的水平依次为:(80.35±29.34)和(115.18±48.69)ng/mL、(658.35±201.19)和(405.36±154.42)pg/mL以及(155.82±40.29)和(229.35±72.46)pg/mL,两组比较差异有统计学意义(P<0.05)。Spearman相关性分析显示,骨转移乳腺癌患者血清中VDBP水平与乳腺癌病理分级相关(P<0.05);FGF23和Klotho水平与病理分级、是否骨痛以及转移部位有关(P<0.05)。VDBP、FGF23和Klotho水平均为乳腺癌骨转移发生的独立影响因素(P<0.05)。ROC曲线结果显示,VDBP、FGF23及Klotho预测乳腺癌患者发生骨转移的曲线下面积依次为:0.733、0.806、0.761,最佳截断值为:81.56 ng/mL、573.501 pg/mL和201.193 pg/mL;3个指标联合诊断的曲线下面积为0.820,高于单一指标诊断的曲线下面积。结论血清VDBP、FGF23及Klotho水平可作为乳腺癌骨转移的参考指标,在乳腺癌骨转移的临床诊断上具有一定应用前景。

Growth factor-and cytokine-driven pathways governing liver stemness and differentiation

Liver is unique in its capacity to regenerate in response to injury or tissue loss. Hepatocytes and other liver cells are able to proliferate and repopulate the liver. However, when this response is impaired, the contribution of hepatic progenitors becomes very relevant. Here, we present an update of recent studies on growth factors and cytokine-driven intracellular pathways that govern liver stem/pro-genitor cell expansion and differentiation, and the rel-evance of these signals in liver development, regeneration and carcinogenesis. Tyrosine kinase receptor signaling, in particular, c-Met, epidermal growth factor receptors or fibroblast growth factor receptors, contribute to prolifera-tion, survival and differentiation of liver stem/progenitor cells. Different evidence suggests a dual role for the trans-forming growth factor (TGF)-β signaling pathway in liver stemness and differentiation. On the one hand, TGF-βmediates progression of differentiation from a progenitor stage, but on the other hand, it contributes to the expan-sion of liver stem cells. Hedgehog family ligands are nec-essary to promote hepatoblast proliferation but need to be shut off to permit subsequent hepatoblast differentiation. In the same line, the Wnt family and β-catenin/T-cell fac-tor pathway is clearly involved in the maintenance of liver stemness phenotype, and its repression is necessary for liver differentiation during development. Collectively, data indicate that liver stem/progenitor cells follow their own rules and regulations. The same signals that are essential for their activation, expansion and differentiation are good candidates to contribute, under adequate conditions, to the paradigm of transformation from a pro-regenerative to a pro-tumorigenic role. From a clinical perspective, this is a fundamental issue for liver stem/progenitor cell-based therapies.

小于胎龄儿生后血清Klotho和成纤维细胞生长因子23水平变化及其与生长发育的关系

目的:探讨小于胎龄儿(SGA)生后血清Klotho和成纤维细胞生长因子23(FGF23)水平变化,并阐明其与生长发育的关系。方法:选取35例SGA和53例适于胎龄儿(AGA)作为研究对象,分为SGA组(n=35)和AGA组(n=53),其中早产儿组51例,早产SGA组20例,早产AGA组31例;足月儿组37例,足月SGA组15例,足月AGA组22例。收集各组新生儿的临床资料,分别检测新生儿生后第7和14天血清Klotho和FGF23水平及临床生化指标,分析新生儿生后第7和14天血清Klotho及FGF23水平与新生儿体质量、身长、头围、胸围和考普氏(Kapu)指数等各项生长发育指标及钙磷代谢的相关性。结果:与AGA组比较,SGA组新生儿出生体质量、身长、头围、胸围和Kapu指数均明显降低(P<0.05)。生后第7和14天,与早产儿组比较,足月儿组新生儿血清Klotho和FGF23水平均明显升高(P<0.01);与生后第7天比较,生后第14天早产儿组和足月儿组新生儿血清Klotho水平均明显升高(P<0.01),FGF23水平均明显降低(P<0.01)。与AGA组比较,SGA组新生儿生后第7和14天血清Klotho和FGF23水平明显降低(P<0.05或P<0.01);与生后第7天比较,生后第14天AGA组和SGA组新生儿血清Klotho水平明显升高(P<0.01),FGF23水平明显降低(P<0.05或P<0.01)。与早产AGA组比较,早产SGA组新生儿生后第7和14天血清Klotho和FGF23水平均明显降低(P<0.05或P<0.01)。与足月AGA组比较,足月SGA组新生儿生后第7和14天血清Klotho和FGF23水平均明显降低(P<0.05或P<0.01)。SGA组新生儿生后第7天血清Klotho和FGF23水平与胎龄、体质量、身长、头围、胸围和Kapu指数等生长发育指标均呈正相关关系(P<0.05或P<0.01),血清Klotho水平与FGF23水平呈正相关关系(P<0.05)。钙磷代谢方面,SGA组新生儿生后第7天血清Klotho水平与血清磷水平呈正相关关系(P<0.01);FGF23水平与血清钙和磷水平均呈正相关关系(P<0.05或P<0.01)。结论:Klotho和FGF23蛋白与新生儿生长发育及磷酸盐代谢有密切关联。SGA新生儿生后血清Klotho和FGF23水平较低,但随着各器官发育逐渐完善,Klotho分泌增加,而FGF23水平降低可能是机体的代偿性反应。

血清成纤维细胞生长因子23、S100A12对老年糖尿病患者动脉粥样硬化性心血管病的预测价值

目的探讨血清成纤维细胞生长因子23(FGF23)、S100A12对老年糖尿病患者动脉粥样硬化性心血管病(ASCVD)的预测价值。方法选取133例老年糖尿病患者为研究对象,根据是否合并ASCVD,将其分为糖尿病组(n=59)和ASCVD组(n=74)。选取同期行体检的健康者为对照组(n=56)。检测并比较血清FGF23、S100A12表达水平。采用多因素Logistic回归分析法分析老年糖尿病患者发生ASCVD的影响因素。评估血清FGF23、S100A12水平对ASCVD发生的预测价值。结果ASCVD组高血压比例、空腹血糖、糖尿病病程高于或长于糖尿病组,差异有统计学意义(P<0.05)。ASCVD组血清FGF23、S100A12表达水平高于糖尿病组、对照组,差异有统计学意义(P<0.05)。高血压、血清FGF23、S100A12表达水平是影响老年糖尿病患者发生ASCVD的独立影响因素(P<0.05)。血清FGF23、S100A12单独预测老年糖尿病患者发生ASCVD的曲线下面积(AUC)分别为0.755、0.874,二者联合预测的AUC为0.934,灵敏度和特异度分别为82.43%、89.83%。血清FGF23、S100A12联合预测优于其单独预测(P<0.05)。结论老年糖尿病患者的血清FGF23、S100A12水平均升高。血清FGF23、S100A12联合预测老年糖尿病患者发生ASCVD的价值相较单独预测更高。

血清ANGPTL3、FGF-23水平与急性脑梗死患者病情严重程度及预后的关系

目的探讨血清血管生成素样蛋白3(ANGPTL3)、成纤维细胞生长因子-23(FGF-23)水平与急性脑梗死(ACI)患者病情严重程度及预后的关系。方法选取2022年3月至2023年2月该院收治的102例ACI患者为ACI组,根据脑梗死体积分为小梗死组、中梗死组和大梗死组,根据美国国立卫生研究院卒中量表(NIHSS)评分分为轻度损伤组、中度损伤组和重度损伤组,根据随访90 d后患者预后情况[改良Rankin量表(mRS)评分]分为预后良好组和预后不良组。另招募同期在该院体检的100例健康者作为对照组。采用酶联免疫吸附试验检测血清ANGPTL3、FGF-23水平。绘制受试者工作特征(ROC)曲线分析血清ANGPTL3、FGF-23对ACI患者预后不良的预测价值。采用Pearson相关分析血清ANGPTL3、FGF-23水平与NIHSS评分及mRS评分的相关性,采用Spearman相关分析血清ANGPTL3、FGF-23水平与脑梗死体积的相关性。结果ACI组血清ANGPTL3、FGF-23水平显著高于对照组(P<0.05)。根据脑梗死体积将ACI患者分为小梗死组29例,中梗死组46例,大梗死组27例;大梗死组血清ANGPTL3、FGF-23水平显著高于小梗死组、中梗死组(P<0.05),中梗死组血清ANGPTL3、FGF-23水平显著高于小梗死组(P<0.05)。根据NIHSS评分将ACI患者分为轻度损伤组41例,中度损伤组38例,重度损伤组23例;重度损伤组血清ANGPTL3、FGF-23水平显著高于轻度损伤组、中度损伤组(P<0.05),中度损伤组血清ANGPTL3、FGF-23水平高于轻度损伤组(P<0.05)。根据随访结果将ACI患者分为预后良好组68例,预后不良组34例;预后不良组血清ANGPTL3、FGF-23水平显著高于预后良好组(P<0.05)。ROC曲线分析结果显示,血清ANGPTL3、FGF-23单独及联合预测ACI患者预后不良的曲线下面积(AUC)分别为0.795、0.856、0.923,灵敏度分别为70.59%、67.65%、88.24%,特异度分别为83.82%、91.18%、82.59%,且二者联合预测ACI患者预后不良的AUC显著高于各项指标单独预测(ZANGPTL3=3.232,P<0.05;Z_(FGF)-23=2.216,P<0.05)。相关性分析结果显示,ACI患者血清ANGPTL3、FGF-23水平与NIHSS评分、脑梗死体积及mRS评分均呈正相关(P<0.05)。结论ACI患者血清ANGPTL3、FGF-23水平上升,且与梗死体积、神经功能缺损严重程度和预后相关,二者联合检测可有效预测ACI预后情况。

连接蛋白2和FGF23在房颤介导心肌病兔心房组织中的表达

目的 探究连接蛋白2(JP2)和成纤维细胞生长因子23(FGF23)在房颤介导心肌病(AMC)兔中的表达规律。方法 通过左心房快速起搏法建立心房颤动(AF)模型,4周后行超声心动图检查,射血分数下降>10%纳入AMC组,否则为AF组,对照组只植入起搏器不起搏。最终成功建立AF动物模型11只,其中AF组6只,AMC组5只,对照组6只。超声心动图检测左室舒张末期内径(LVEDD)、左室收缩末期内径(LVESD)、左室射血分数(LVEF)等指标,酶联免疫吸附法(ELISA)检测血清JP2和FGF23水平。处死动物后,取心房组织,Western blot和RT-qPCR检测JP2和FGF23蛋白及mRNA表达。结果 与对照组相比,AMC组左房内径、右房内径、右室内径增大,LVEF降低,与AF组相比,AMC组LVEF降低,主动脉增宽,右室扩大。与对照组相比,AF组左房心肌细胞FGF23(P<0.001)、JP2(P<0.01)的表达均明显增加,而AMC组JP2表达降低(P<0.001)。与AF组相比,AMC组FGF23和JP2的表达下降。与对照组相比,AF组FGF23和JP2血浆浓度升高,AMC组FGF23水平升高。与AF组相比,AMC组FGF23和JP2血浆浓度偏低。结论 在AMC兔模型中,FGF23表达增加,JP2表达下降。

狼疮性肾炎患者血清FGF-23、Gas6水平与疾病活动性的关系

目的探讨狼疮性肾炎(LN)患者血清成纤维细胞生长因子23(FGF-23)、生长停滞特异性蛋白6(Gas6)水平与疾病活动性的关系。方法选择2021年3月—2024年3月延安市人民医院风湿免疫科收治的LN患者119例为LN组,并根据系统性红斑狼疮疾病活动指数2000(SLEDAI-2000)评分分为活动亚组70例和非活动亚组49例,另选取同期医院健康体检者105例为健康对照组。采用酶联免疫吸附试验检测血清FGF-23、Gas6水平;Pearson相关分析血清FGF-23、Gas6水平与肾功能指标、SLEDAI-2000评分的相关性;多因素Logistic回归分析LN患者疾病活动性的影响因素;受试者工作特征(ROC)曲线评价血清FGF-23、Gas6水平对LN患者疾病活动性的诊断价值。结果LN组血清FGF-23、Gas6水平均高于健康对照组(t/P=21.040/<0.001、7.389/<0.001);活动亚组收缩压、舒张压、尿素氮(BUN)、血肌酐(SCr)、尿蛋白、SLEDAI-2000评分、FGF-23、Gas6均高于非活动亚组(t/P=2.356/0.020、3.717/<0.001、11.867/<0.001、17.152/<0.001、30.579/<0.001、19.439/<0.001、11.284/<0.001、10.818/<0.001),补体C3、C4水平低于非活动亚组(t/P=6.233/<0.001、12.329/<0.001);血清FGF-23、Gas6水平分别与BUN、SCr、尿蛋白、SLEDAI-2000评分呈正相关(FGF-23:r/P=0.410/<0.001、0.395/<0.001、0.326/0.002、0.563/<0.001;Gas6:r/P=0.352/<0.001、0.384/<0.001、0.311/0.008、0.509/<0.001),与补体C3、C4水平呈负相关(FGF-23:r/P=-0.408/<0.001、-0.377/<0.001;Gas6:r/P=-0.376/<0.001、-0.321/<0.001);多因素Logistic回归分析显示,高FGF-23、Gas6、尿蛋白水平是LN患者疾病活动的独立危险因素[OR(95%CI)=2.136(1.224~3.727)、1.865(1.171~2.967)、2.539(1.416~4.554)];血清FGF-23、Gas6水平及二者联合诊断LN患者疾病活动性的曲线下面积(AUC)分别为0.804、0.834、0.938,二者联合的AUC大于各自单独诊断(Z/P=3.843/<0.001、3.270/<0.001)。结论LN患者血清FGF-23、Gas6水平均增高,且与LN肾功能损伤、补体水平降低及疾病活动性增加有关。联合检测FGF-23、Gas6可有效鉴别LN疾病活动性。