GROWTH DIFFERENTIATION FACTOR-5 STIMULATES THE GROWTH AND ANABOLIC METABOLISM OF ARTICULAR CHONDROCYTES

Objective To observe the effect of growth differentiation factor-5 (GDF-5) on the growth and anabolic metabolism of articular chondrocytes. Methods The articular chondrocytes isolated from rats were treated with various concentrations of rmGDF-5, and the growth of chondrocytes measured by MTT assay, the cellular cartilage matrices formation detected sulfated glycosaminoglycan by Alcian blue staining and type Ⅱcollagen by RT-PCR. Results After 7 days culture, MTT assay showed that GDF-5 enhanced the growth of chondrocytes in a dose-dependent manner, RT-PCR showed that GDF-5 clearly induced the synthesis of type Ⅱ collagen because of the col2a1 mRNA band more and more strong in a dose-dependent. Chondrocytes were cultured with GDF-5 for 14 days, the intensity of Alcian blue staining was greatly enhanced, especially, at a high concentration of 1000ng/mL, and GDF-5 enhanced the accumulation of the Alcian blue-stainable material in a concentration-dependent manner and in a does-dependent manner. Conclusion GDF-5 enhanced the growth of mature articular chondrocytes, and stimulated the cellular cartilage matrices formation in mono-layer culture.

Correlation between growth differentiation factor-15 and collagen metabolism indicators in patients with myocardial infarction and heart failure

BackgroundGrowth differentiation factor （GDF）-15, a divergent member of the transforming growth factor beta super-family does appear to be up-regulated in response to experimental pressure overload and progression of heart failure （HF）. HF frequently develops after myocardial infarction （MI）, contributing to worse outcome. The aim of this study is to assess the correlation between GDF-15 levels and markers related to collagen turnover in different stages of HF.MethodsThe study consists of a cohort of 179 patients, including stable angina pectoris patients （AP group,n= 50）, old MI patients without HF （OMI group,n = 56）, old MI patients with HF （OMI-HF group,n= 38） and normal Control group （n = 35）. Both indicators reflecting the synthesis and degradation rates of collagen including precollagen I N-terminal peptide （PINP）, type I collagen carboxy-terminal peptide （ICTP）, precollagen III N-terminal peptide （PIIINP） and GDF-15 were measured using an enzyme-linked inmunosorbent assay.ResultsThe plasma GDF-15 level was higher in OMI-HF group （1373.4 ± 275.4 ng/L） than OMI group （1036.1 ± 248.6 ng/L）, AP group （784.6 ± 222.4 ng/L） and Control group （483.8 ± 186.4 ng/L） （P〈 0.001）. The indi-cators of collagen turnover （ICTP, PINP, PIIINP） all increased in the OMI-HF group compared with Control group （3.03 ± 1.02μg/Lvs. 2.08 ± 0.95μg/L, 22.2 ± 6.6μg/Lvs. 16.7 ± 5.1μg/L and 13.2 ± 7.9μg/Lvs. 6.4 ± 2.1μg/L, respectively;P〈 0.01）. GDF-15 positively cor-related with ICTP and PIIINP （r = 0.302,P〈 0.001 andr= 0.206,P= 0.006, respectively）. GDF-15 positively correlated to the echocardio-graphic diastolic indicators E/Em and left atrial pressure （r= 0.349 and r= 0.358, respectively;P〈 0.01）, and inversely correlated to the systolic indicators left ventricular ejection fraction and the average of peak systolic myocardial velocities （Sm） （r=-0.623 and r=-0.365, respectively;P〈 0.01）.ConclusionPlasma GDF-15 is associated with the indicators of type I and III collagen turnover.

Growth differentiation factor-15 is a prognostic marker in patients with intermediate coronary artery disease

Background Growth differentiation factor-15(GDF-15)is involved in multiple processes that are associated with coronary artery disease(CAD).However,little is known about the association between GDF-15 and the future ischemic events in patients with intermediate CAD.This study was conducted to investigate whether plasma GDF-15 constituted risk biomarkers for future cardiovascular events in patients with intermediate CAD.Methods A prospective study was performed based on 541 patients with intermediate CAD(20%–70%).GDF-15 of each patient was determined in a blinded manner.The primary endpoint was major adverse cardiac event(MACE),which was defined as a composite of all-cause death,nonfatal myocardial infarction,revascularization and readmission due to angina pectoris.Results After a median follow-up of 64 months,504 patients(93.2%)completed the follow-up.Overall,the combined endpoint of MACE appeared in 134 patients(26.6%)in the overall population:26 patients died,11 patients suffered a nonfatal myocardial infarction,51 patients underwent revascularization,and 46 patients were readmitted for angina pectoris.The plasma levels of GDF-15(median:1172.02 vs.965.25 pg/m L,P=0.014)were higher in patients with ischemic events than those without events.After adjusting for traditional risk factors,higher GDF-15 levels were significantly associated with higher incidence of the composite endpoint of MACE(HR=1.244,95%CI:1.048–1.478,Quartile 4 vs.Quartile 1,P=0.013).Conclusions The higher level of GDF-15 was an independent predictor of long-term adverse cardiovascular events in patients with intermediate CAD.

Growth differentiation factor 5:a neurotrophic factor with neuroprotective potential in Parkinson’s disease

Parkinson’s disease is the most common movement disorder worldwide,affecting over 6 million people.It is an age-related disease,occurring in 1%of people over the age of 60,and 3%of the population over 80 years.The disease is characterized by the progressive loss of midbrain dopaminergic neurons from the substantia nigra,and their axons,which innervate the striatum,resulting in the characteristic motor and non-motor symptoms of Parkinson’s disease.This is paralleled by the intracellular accumulation ofα-synuclein in several regions of the nervous system.Current therapies are solely symptomatic and do not stop or slow disease progression.One promising disease-modifying strategy to arrest the loss of dopaminergic neurons is the targeted delivery of neurotrophic factors to the substantia nigra or striatum,to protect the remaining dopaminergic neurons of the nigrostriatal pathway.However,clinical trials of two well-established neurotrophic factors,glial cell line-derived neurotrophic factor and neurturin,have failed to meet their primary end-points.This failure is thought to be at least partly due to the downregulation byα-synuclein of Ret,the common co-receptor of glial cell line-derived neurorophic factor and neurturin.Growth/differentiation factor 5 is a member of the bone morphogenetic protein family of neurotrophic factors,that signals through the Ret-independent canonical Smad signaling pathway.Here,we review the evidence for the neurotrophic potential of growth/differentiation factor 5 in in vitro and in vivo models of Parkinson’s disease.We discuss new work on growth/differentiation factor 5’s mechanisms of action,as well as data showing that viral delivery of growth/differentiation factor 5 to the substantia nigra is neuroprotective in theα-synuclein rat model of Parkinson’s disease.These data highlight the potential for growth/differentiation factor 5 as a disease-modifying therapy for Parkinson’s disease.

Chondrogenic differentiation of human bone mesenchymal stem cells treated with growth differentiation factor 5 under hypoxia

Objective To explore the feasibility and effectiveness of the self-assembly cartilage tissue engineered with chondrogenically differentiated human bone mesenchymal stem cells (hBMCs) induced by growth differentiation factor-5 (GDF-5)

血清GDF5 mRNA在慢性牙周炎患者中的水平及其与病变程度的相关性

目的分析血清生长分化因子5(GDF5)mRNA在慢性牙周炎患者中的水平及其与病变程度的相关性。方法选取2019年1月至2021年1月该院口腔科收治的慢性牙周炎患者150例作为研究组,并根据牙周检查情况分为轻度组(53例),中度组(51例),重度组(46例),另选取同期健康体检者50例作为对照组;采用实时荧光定量聚合酶链反应(qRT-PCR)检测血清GDF5 mRNA水平;采用Pearson相关分析血清GDF5 mRNA水平与牙周袋探诊深度、附着丧失水平和菌斑指数的相关性;采用Spearman相关分析GDF5 mRNA水平与病变程度的相关性;采用多因素Logistic回归分析慢性牙周炎的影响因素;绘制受试者工作特征(ROC)曲线分析血清GDF5 mRNA水平对重度慢性牙周炎的预测价值。结果对照组与研究组GDF5 mRNA水平分别为1.01±0.30、0.70±0.21,研究组明显低于对照组,差异有统计学意义(t=8.061,P<0.001)。血清GDF5 mRNA水平、牙周袋探诊深度、附着丧失水平和菌斑指数在轻度组、中度组和重度组中依次升高,两两组间比较,差异均有统计学意义(P<0.05)。GDF5 mRNA与牙周袋探诊深度、附着丧失水平、菌斑指数、病变程度均呈负相关(r=-0.587、-0.521、-0.628、-0.567,P<0.001)。多因素Logistic回归分析结果显示,GDF5 mRNA水平降低是慢性牙周炎发生的危险因素(P<0.05)。ROC曲线分析结果显示,血清GDF5 mRNA预测重度慢性牙周炎的曲线下面积为0.893,灵敏度为79.23%,特异度为88.31%。结论慢性牙周炎患者血清GDF5 mRNA水平随着病变程度的加重而降低,GDF5 mRNA还可以作为预测重度慢性牙周炎的指标。

生长分化因子5与代谢性疾病

生长分化因子5(growth/differentiation factor-5,GDF-5)属于转化生长因子β(transforming growth factor-β,TGF-β)家族,在骨、软骨、心脏、大脑、肾脏、骨骼肌和肌腱、肝脏以及脂肪等多个器官组织中表达。GDF-5与其受体BMPR-I/BMPR-II结合,激活Smad1/5/8、PI3K/Akt、p38-MAPK等信号,发挥促进细胞增殖分化、减少氧化应激损伤、细胞凋亡和组织纤维化等生物学功能。目前针对GDF-5的研究多聚焦在骨、软骨与肌腱的生长和修复等方面,而在其他器官中的生物学作用鲜有报道。因此,本文通过梳理和总结近年来GDF-5与代谢性疾病的研究进展,为GDF-5在改善代谢性疾病防治提供新的见解和理论依据。

双膦酸盐修饰生长分化因子5促进MC3T3-E1细胞的成骨分化

背景:生长分化因子5作为骨形态发生蛋白的一员在软骨及骨组织修复领域表现出良好的应用潜力,增强生长分化因子5与骨组织的亲和力是提高蛋白使用效率的关键,因而开发具有骨靶向性的生长分化因子5蛋白具有重要意义。目的:利用双膦酸盐修饰生长分化因子5并探讨改性后蛋白对小鼠成骨前体细胞生长分化的影响。方法:采用化学交联法将生长分化因子5与帕米膦酸钠偶联,得到偶联帕米膦酸钠的生长分化因子5,采用傅里叶变换红外光谱、圆二色谱对其基团及结构进行表征,利用ELISA试剂盒测定生长分化因子5与磷酸钙的结合量以及生长分化因子5的体外释放量,用于表征其体外骨靶向性。将生长分化因子5(对照组)、偶联帕米膦酸钠的生长分化因子5(实验组)分别与成骨前体细胞MC3T3-E1共培养,以单独培养的细胞为空白对照,评价复合物对细胞增殖及分化等的影响。结果与结论:①红外光谱及圆二色谱结果表明,实验成功制备了双膦酸盐/生长分化因子5复合物且蛋白二级结构无显著变化;体外磷酸钙吸附结果表明,偶联帕米膦酸钠后,生长分化因子5与磷酸钙的吸附率增加了约1倍;在半胱氨酸存在条件下,偶联帕米膦酸钠的生长分化因子5的蛋白可释放出来;②CCK-8实验结果显示,实验组培养4,7 d的吸光度值高于对照组、空白对照组(P<0.0001);培养7 d后,实验组碱性磷酸酶表达明显高于对照组、空白对照组(P<0.0001);培养13 d后,实验组钙结节含量明显高于对照组、空白对照组(P<0.0001);qRT-PCR结果检测结果显示,培养7 d后,实验组碱性磷酸酶、骨钙素及Runx2的mRNA表达高于对照组、空白对照组(P<0.01,P<0.001,P<0.0001);③结果表明,双膦酸盐修饰有利于增强生长分化因子5与磷酸钙的结合能力,同时有利于增强其生物活性。

生长分化因子5诱导兔骨髓间充质干细胞的软骨分化

背景:生长分化因子5属于转化生长因子超家族成员之一,也是关节发育的最早标志之一,对软骨修复具有重要作用。目的:探讨生长分化因子5诱导骨髓间充质干细胞向软骨分化的作用机制。方法:分离培养兔骨髓间充质干细胞,CCK-8法检测不同质量浓度生长分化因子5对骨髓间充质干细胞增殖活性的影响,RT-PCR检测不同质量浓度生长分化因子5诱导骨髓间充质干细胞成软骨分化相关基因的表达;为进一步探讨生长分化因子5诱导骨髓间充质干细胞成软骨分化的作用机制,加入Wnt/β-catenin信号通路抑制剂XAV-939和激活剂Laduviglusib诱导培养14 d,RT-PCR和Western blot检测软骨相关基因和Wnt/β-catenin信号通路中相关蛋白的表达。结果与结论:①CCK-8结果表明生长分化因子5对骨髓间充质干细胞增殖没有明显影响;②生长分化因子5促进了软骨相关基因Ⅱ型胶原、蛋白聚糖、Sox9的表达,其中以50 ng/mL组软骨相关基因上调明显;③加入Wnt/β-catenin信号通路激活剂Laduviglusib之后,Sox9、β-catenin和Ⅱ型胶原表达上调(P<0.05),加入Wnt/β-catenin信号通路抑制剂XAV939之后,Sox9、β-catenin和Ⅱ型胶原表达下调(P<0.05);④综上,生长分化因子5诱导骨髓间充质干细胞向软骨分化可能与激活Wnt/β-catenin信号通路有关。

生长分化因子5诱导间充质干细胞多向分化的作用与问题

背景:生长分化因子5属于转化生长因子β超家族成员和骨形态发生蛋白家族成员之一,在关节软骨损伤修复、骨再生、改善椎间盘退行性变、肌腱愈合和神经发育等方面发挥重要作用。目的:综述生长分化因子5诱导软骨细胞、髓核样细胞、肌腱细胞分化以及诱导骨形成和神经发育方面的研究进展。方法:在中国知网、万方数据库,以“生长分化因子5,关节软骨,骨,髓核样细胞,肌腱,神经再生”为检索词;在PubMed数据库以“growth differentiation factor 5,articular cartilage,bone,nucleus pulposus cells,tendon,nerve regeneration”为检索词进行检索。根据纳入与排除标准,排除与主题内容不相关的文献,纳入与生长分化因子5相关的69篇文献。结果与结论:①生长分化因子5可诱导间充质干细胞成软骨和成骨分化,但是生长分化因子5诱导成软骨或成骨分化的浓度分界仍然不清楚;②生长分化因子5可诱导间充质干细胞向髓核细胞分化,可能对治疗椎间盘退行性变有一定作用;③生长分化因子5能够诱导间充质干细胞向肌腱细胞分化,对肌腱损伤修复及预防术后肌腱粘连发挥重要作用;④生长分化因子5可诱导神经发育,促进神经再生。

Effect of the gap junction blocker 1-heptanol on chondrogenic differentiation of mouse bone marrow mesenchymal stem cells in vitro

Objective：To investigate the effect of the gap junction blocker 1-heptanol on the in vitro chondrogenic differentiation of mouse bone marrow mesenchymal stem cells（MSCs） following induction by GDF-5. Methods：MSCs were isolated from mouse bone marrow and cultured in vitro. After 3 passages cells were induced to undergo chondrogenic differentiation with recombinant human GDF-5（100 ng/ml）, with or without 1-heptanol（2.5 la mol/L）. The effect of 1-heptanol on MSCs proliferation was investigated using the MTT assay. Type II collagen mRNA and protein were examined by RT-PCR and immunocytochemistry respectively, and the sulfate glycosaminoglycan was assessed by Alcian blue dye staining. Connexin43（Cx43） protein was examined by western blotting. Results：GDF-5 induced proliferation and chondrogenic differentiation of MSCs. While 1-heptanol treatment had no effect on this proliferation, it inhibited the expression of both type II collagen mRNA and protein. The Alcian blue staining revealed that 1-heptanol also inhibited the deposition of the typical cartilage extracellular matrix promoted by recombinant GDF-5. Western blotting demonstrated that 1-heptanol had no effect on the expression of Cx43. Conclusion：These results suggest that mouse bone marrow MSCs can be differentiated into a chondrogenic phenotype by GDF- 5 administration in vitro. While the gap junction blocker, 1-heptanol, did not reduce gap junction Cx43, these intercellular communication pathways clearly played an important functional role in GDF-5-induced cartilage differentiation.

Identification of cytokines involved in hepatic differentiation of mBM-MSCs under liver-injury conditions

AIM: To identify the key cytokines involved in hepatic differentiation of mouse bone marrow mesenchymal stem cells (mBM-MSCs) under liver-injury conditions. METHODS: Abdominal injection of CCl4 was adopted to duplicate a mouse acute liver injury model. Global gene expression analysis was performed to evaluate the potential genes involved in hepatic commitment under liver-injury conditions. The cytokines involved in hepatic differentiation of mBM-MSCs was function-ally examined by depletion experiment using specifi c antibodies, followed by rescue experiment and direct inducing assay. The hepatic differentiation was characterized by the expression of hepatic lineage genes and proteins, as well as functional features. RESULTS: Cytokines potentially participating in hepatic fate commitment under liver-injury conditions were initially measured by microarray. Among the up-regulated genes determined, 18 cytokines known to closely relate to liver growth, repair and development, were selected for further identif ication. The f ibroblast growth factor-4 (FGF-4), hepatocyte growth factor (HGF) and oncostatin M (OSM) were fi nally found to be involved in hepatic differentiation of mBM-MSCs under liver-injury conditions. Hepatic differentiation could be dramatically decreased after removing FGF-4, HGF and OSM from the liver-injury conditioned medium, and could be rescued by supplementing these cytokines. The FGF-4, HGF and OSM play different roles in the hepatic differentiation of mBM-MSCs, in which FGF-4 and HGF are essential for the initiation of hepatic differentiation, while OSM is critical for the maturation of hepatocytes. CONCLUSION: FGF-4, HGF and OSM are the key cytokines involved in the liver-injury conditioned medium for the hepatic differentiation of mBM-MSCs.

BMP-4 induced proliferation and oriented differentiation of rat hepatic oval cells into hepatocytes

Objective:To explore the role of bone morphogenetic protein 4(BMP-4) in hepatic progenitor cells(HPCs).Methods:The effect of BMP-4 on rat hepatic oval cells was examined by using the WB-F344 rat hepatocytic epithelial stem-cell-like cell line.This hepatocytic cell line could exert various hepatocytc functions including the secretion of albumin and urea.Immunohistochemistry was used to examine the effects of BMP-4 and its antagonist,Noggin,on the proliferation and differentiation of these cells,cellular uptake and excretion of indocyanine green,the periodic acid-schiff(PAS) assay for glycogen storage and the expression of hepatic markers.Results:Our results showed for the first time that BMP-4 may acted as a potential inducer of hepatic differentiation in rat hepatic oval cells.Conclusions:This cell source offers a much-needed attractive and expandable source for future investigations of drug screening,stem cell technologies and cellular transplantation,in a society with increasing levels of liver disease and damage.

All-trans retinoic acid regulates the expression of MMP-2 and TGF-β2 via RDH5 in retinal pigment epithelium cells

·AIM: To investigate the effect of all-trans retinoic acid(ATRA) on retinol dehydrogenase 5(RDH5), matrix metalloproteinase-2(MMP-2) and transforming growth factor-β2(TGF-β2) transcription levels, and the effect of RDH5 on MMP-2 and TGF-β2 in retinal pigment epithelium(RPE) cells.·METHODS: After adult RPE cell line-19(ARPE-19 cells) intervened with gradient concentrations of ATRA(0-20 μmol/L) for 24h, flow cytometry was used to detect the proliferation and apoptosis of cells in each group, and quantitative realtime polymerase chain reaction(q RT-PCR) was used to detect RDH5, MMP-2 and TGF-β2 m RNA expression. Then, after ARPE-19 cells transfected with three different si RNA targets for 48h, the RDH5 knockdown efficiency of each group and expression of MMP-2 and TGF-β2 m RNA within them was detected by q RT-PCR. ·RESULTS: Flow cytometry results showed that ATRA could inhibit the proliferation of RPE cells and promote the apoptosis of RPE cells, and the difference of apoptosis was statistically significant when the ATRA concentration exceeded 5 μmol/L and compared with the normal control group(P=0.027 and P=0.031, respectively). q RT-PCR results showed that ATRA could significantly inhibit the expression level of RDH5 m RNA(P<0.001) and promote the expression of MMP-2 and TGF-β2 m RNA(P=0.03 and P<0.001, respectively) in a dose-dependent manner, especially when treated with 5 μmol/L ATRA. The knockdown efficiency of RDH5 si RNA varies with different targets, among which RDH5 si RNA-435 had the highest knockdown efficiency, i.e., more than 50% lower than that of the negative control group(P=0.02). When RDH5 was knocked down for 48h, the results of q RT-PCR showed that the expressions of MMP-2 and TGF-β2 m RNA were significantly up-regulated(P<0.001).·CONCLUSION: ATRA inhibits the expression of RDH5 and promotes MMP-2 and TGF-β2, and further RDH5 knockdown significantly upregulates MMP-2 and TGF-β2. These findings suggest that RDH5 may be involved in an epithelial-mesenchymal transition of RPE cells mediated by ATRA.

GDF5基因突变导致近端指(趾)骨关节粘连1B型一个家系报告

收集并分析1例因“双侧手指近端指间关节屈曲受限11年,生长缓慢8年”,于河南科技大学第一附属医院内分泌代谢科住院的患儿资料及其家系基因检测结果。基因检测结果显示先证者生长分化因子5(growth/differentiation factor 5, GDF5)基因第2外显子出现杂合错义突变:c.1118T>G(p.L373R),Sanger测序验证显示先证者父亲、祖母均携带该突变。综合临床症状及基因检测结果诊断为近端指(趾)骨关节粘连(proximal symphalangism, SYM)1B。SYM1B致病基因为GDF5基因,主要累及手指/足趾近端关节,可辅助影像学及基因检测确诊该病。

Correlation between expression of two transforming growth factor-beta 1 receptors and microvascular density in a rat model of cerebral ischemia and reperfusion injury

The effects of transforming growth factor-β1 （TGF-β1） are currently controversial. Whether TGF-β1 promotes or inhibits revascularization under different conditions remains poorly understood. Based on previous studies, the current experiment established rat models of cerebral ischemia and reperfusion injury （IRI）, and demonstrated that pathological and functional damage was also increased after IRI. The most serious damage was observed at 3 days after reperfusion, at which time microvascular density fell to its lowest level. Soon afterwards, microvascular density increased, new collateral circulation was gradually established at 4 to 7 days after reperfusion, and pathological damage and neurological deficits were improved. TGF-β1, activin receptor-like kinase 5 （ALK5） mRNA and protein expression levels increased gradually over time. In contrast, ALK1 mRNA and protein expression decreased over the same period. A significant negative correlation was detected between microvascular density and expression of the ALK5 gene transcript. There was no correlation between microvascular density and ALK1 gene transcriptional expression following cerebral IRI in a rat model. These findings suggest that ALK5, rather than ALK1, is the critical receptor in the TGF-β1 signal pathways after cerebral IRI.

生长分化因子5在骨关节炎发生发展中的作用

背景:生长分化因子5属于转化生长因子β和骨形态发生蛋白家族的成员,在关节形成过程中及骨骼和关节软骨发育中发挥重要作用,作为组织工程的细胞因子,对促进骨软骨修复具有巨大潜力。目的:探讨生长分化因子5在骨关节炎中的作用以及所存在的一些问题,以期望生长分化因子5在后续有更多的研究,为骨关节炎的治疗提供理论基础。方法:在中国知网、万方数据库,以“生长分化因子5,关节软骨,细胞迁移,细胞迁移,软骨下骨,炎症,骨关节炎,类风湿性关节炎”为检索词,以及在Pub Med数据库以“growth differentiation factor 5,articular cartilage,cell migration,cell proliferation,subchondral bone,inflammation,osteoarthritis,rheumatoid arthritis”为检索词,检索生长分化因子5与骨关节炎相关作用及机制的文章。结果与结论:(1)生长分化因子5促进间充质干细胞向软骨细胞分化,表达Ⅱ型胶原和蛋白聚糖,维持软骨细胞的特性。(2)生长分化因子5促进软骨细胞肥大分化,但是也有研究表明,生长分化因子5诱导后软骨细胞肥大标志物的表达是降低的,表明其对软骨的修复是利大于弊。(3)生长分化因子5可促进成骨的表达,增加软骨下骨矿化密度,通过软骨下骨的修复来间接促进软骨的修复。(4)炎症因子是促进骨关节炎发生发展的因素之一,生长分化因子5可抑制炎症因子的表达,从而达到保护骨关节炎的目的。生长分化因子5作为一种“多功能”的诱导因子,对软骨、软骨下骨及炎症均有一定作用,但是其作用机制仍然不清楚,探明其相关作用机制,在未来有希望成为一种保护骨关节炎的药物。

镜像疗法联合康复训练对脑梗死偏瘫患者FMA评分、BBS评分和血清GDF-15、Fibulin-5水平的影响

目的观察镜像疗法(MT)联合康复训练对脑梗死偏瘫患者肢体运动功能(FMA)评分、平衡功能(BBS)评分和血清生长分化因子-15(GDF-15)、衰老关键蛋白抗原-5(Fibulin-5)水平的影响。方法选取2020年1月至2022年12月三亚市中医院收治的脑梗死偏瘫患者82例,以随机数表法分为研究组与对照组,各自41例,给予对照组患者常规治疗及康复训练,研究组在对照组基础上予以MT,两组均持续治疗3个月。比较两组临床疗效、治疗前后的FMA评分、BBS评分、下肢肌力、血清GDF-15、Fibulin-5水平。结果治疗后研究组临床疗效的总有效率为90.24%,高于对照组的73.17%,差异有统计学意义(χ^(2)=3.998,P<0.05)。治疗后两组患者上、下肢FMA评分、BBS评分、下肢肌力分级4~5级比例较治疗前增加,且研究组高于对照组,差异有统计学意义(t=2.480、2.419、2.092,Z=3.812,P<0.05)。治疗后两组患者血清GDF-15水平较治疗前降低,且研究组低于对照组,差异有统计学意义(t=2.527,P<0.05);Fibulin-5水平则较治疗前增加,且研究组高于对照组,差异有统计学意义(t=2.062,P<0.05)。结论MT联合康复训练对脑梗死偏瘫患者效果肯定,能有效促进患者躯体功能的恢复,同时有助于改善下肢肌力与血清GDF-15、Fibulin-5水平,具有临床推荐价值。

Growth differentiation factor-15 combined with N-terminal prohormone of brain natriuretic peptide increase 1-year prognosis prediction value for patients with acute heart failure: a prospective cohort study

Background:Clinical assessment and treatment guidance for heart failure depends on a variety of biomarkers.The objective of this study was to investigate the prognostic predictive value of growth differentiation factor-15(GDF-15)and N-terminal prohormone of brain natriuretic peptide(NT-proBNP)in assessing hospitalized patients with acute heart failure(AHF).Methods:In total,260 patients who were admitted for AHF in the First Affiliated Hospital of Nanjing Medical University were enrolled from April 2012 to May 2016.Medical history and blood samples were collected within 24 h after the admission.The primary endpoint was the all-cause mortality within 1 year.The patients were divided into survival group and death group based on the endpoint.With established mortality risk factors and serum GDF-15 level,receiver-operator characteristic(ROC)analyses were performed.Cox regression analyses were used to further analyze the combination values of NT-proBNP and GDF-15.Results:Baseline GDF-15 and NT-proBNP were significantly higher amongst deceased than those in survivors(P<0.001).In ROC analyses,area under curve(AUC)for GDF-15 to predict 1-year mortality was 0.707(95%confidence interval[CI]:0.648–0.762,P<0.001),and for NT-proBNP was 0.682(95%CI:0.622–0.738,P<0.001).No statistically significant difference was found between the two markers(P=0.650).Based on the optimal cut-offs(GDF-15:4526.0 ng/L;NT-proBNP:1978.0 ng/L),the combination of GDF-15 and NT-proBNP increased AUC for 1-year mortality prediction(AUC=0.743,95%CI:0.685–0.795,P<0.001).Conclusions:GDF-15,as a prognostic marker in patients with AHF,is not inferior to NT-proBNP.Combining the two markers could provide an early recognition of high-risk patients and improve the prediction values of AHF long-term prognosis.Clinical trial registration:ChiCTR-ONC-12001944,http://www.chictr.org.cn.

Growth Differentiation Factor-15 Produces Analgesia by Inhibiting Tetrodotoxin-Resistant Nav1.8 Sodium Channel Activity in Rat Primary Sensory Neurons

Growth differentiation factor 15(GDF-15)is a member of the transforming growth factor-βsuperfamily.It is widely distributed in the central and peripheral nervous systems.Whether and how GDF-15 modulates nociceptive signaling remains unclear.Behaviorally,we found that peripheral GDF-15 significantly elevated nociceptive response thresholds to mechanical and thermal stimuli in naïve and arthritic rats.Electrophysiologically,we demonstrated that GDF-15 decreased the excitability of small-diameter dorsal root ganglia(DRG)neurons.Furthermore,GDF-15 concentration-dependently suppressed tetrodotoxin-resistant sodium channel Nav1.8 currents,and shifted the steady-state inactivation curves of Nav1.8 in a hyperpolarizing direction.GDF-15 also reduced window currents and slowed down the recovery rate of Nav1.8 channels,suggesting that GDF-15 accelerated inactivation and slowed recovery of the channel.Immunohistochemistry results showed that activin receptor-like kinase-2(ALK2)was widely expressed in DRG medium-and small-diameter neurons,and some of them were Nav1.8-positive.Blockade of ALK2 prevented the GDF-15-induced inhibition of Nav1.8 currents and nociceptive behaviors.Inhibition of PKA and ERK,but not PKC,blocked the inhibitory effect of GDF-15 on Nav1.8 currents.These results suggest a functional link between GDF-15 and Nav1.8 in DRG neurons via ALK2 receptors and PKA associated with MEK/ERK,which mediate the peripheral analgesia of GDF-15.