Study of growth differentiation factor-15 in polytransfused children with ?-thalassemia

Background: Ineffective erythropoiesis is a predominant feature in ?-thalassemia major (?-TM), causing marked erythroid expansion leading to highly raised levels of growth differentiation factor-15 (GDF-15), which, in turn, suppresses hepcidin production in liver resulting in increased iron absorption from gut. We aim to study the serum GDF-15 in polytransfused ?-TM patients and its correlation with serum ferritin and serum hepcidin. Method: Thirty-nine polytransfused ?-TM children aged between 5 and 17 years and 33 age- and gender-matched healthy controls were enrolled in the study. Complete blood count, serum GDF-15, serum ferritin, and serum hepcidin were performed. Results: The mean serum GDF-15, serum hepcidin, and serum ferritin levels were 638.65 ± 306.96 pg/ml, 108.21 ± 191.30 ng/ml, and 2274.60 ± 1216.08 ng/ml, respectively, which were significantly higher than control group (P < 0.001, P = 0.003, P < 0.001, respectively). There was significant positive correlation of GDF-15 with blood transfusions (r = 0.415, P = 0.009), positive correlation with serum ferritin (r = 0.653, P = 0), and significant negative correlation with serum hepcidin (r = ?0.508, P = 0.001). Conclusion: The findings of the present study suggest that GDF-15 is an important regulator of hepcidin in ?-TM patients. GDF-15 and serum hepcidin together can be used to monitor iron overload and its related complications in such patients.

GDF15 negatively regulates chemosensitivity via TGFBR2-AKT pathway-dependent metabolism in esophageal squamous cell carcinoma / 医学前沿

Treating patients with esophageal squamous cell carcinoma (ESCC) is challenging due to the high chemoresistance. Growth differentiation factor 15 (GDF15) is crucial in the development of various types of tumors and negatively related to the prognosis of ESCC patients according to our previous research. In this study, the link between GDF15 and chemotherapy resistance in ESCC was further explored. The relationship between GDF15 and the chemotherapy response was investigated through in vitro and in vivo studies. ESCC patients with high levels of GDF15 expression showed an inferior chemotherapeutic response. GDF15 improved the tolerance of ESCC cell lines to low-dose cisplatin by regulating AKT phosphorylation via TGFBR2. Through an in vivo study, we further validated that the anti-GDF15 antibody improved the tumor inhibition effect of cisplatin. Metabolomics showed that GDF15 could alter cellular metabolism and enhance the expression of UGT1A. AKT and TGFBR2 inhibition resulted in the reversal of the GDF15-induced expression of UGT1A, indicating that TGFBR2-AKT pathway-dependent metabolic pathways were involved in the resistance of ESCC cells to cisplatin. The present investigation suggests that a high level of GDF15 expression leads to ESCC chemoresistance and that GDF15 can be targeted during chemotherapy, resulting in beneficial therapeutic outcomes.

GDF-15 como Biomarcador em Doenças Cardiovasculares / GDF-15 as a Biomarker in Cardiovascular Disease

Resumo Nos últimos anos, vários biomarcadores estão ganhando importância clínica na avaliação diagnóstica e prognóstica de pacientes com doenças cardiovasculares. O fator de crescimento e diferenciação celular-15 (GDF-15) é uma citocina induzida por estresse e inflamação, membro da família do TGF-, cuja produção no miocárdio foi demonstrada experimentalmente em resposta à injúria isquêmica ou sobrecarga cardíaca. Este novo marcador foi positivamente correlacionado com aumento do risco de eventos cardiovasculares em estudos populacionais e configurou-se preditor independente de mortalidade e prognóstico adverso em pacientes com doença arterial coronariana e insuficiência cardíaca. Este trabalho tem como objetivo revisar o valor diagnóstico e prognóstico do GDF-15 em diferentes cenários na cardiologia.

Abstract In the last years, several diagnostic and prognostic biomarkers have been studied in cardiovascular disease. Growth differentiation factor-15 (GDF-15), a cytokine belonging to the transforming growth factor- (TGF-) family, is highly up-regulated in stress and inflammatory conditions and has been correlated to myocardial injury and pressure cardiac overload in animal models. This new biomarker has been positively correlated with increased risk of cardiovascular events in population studies and shown an independent predictor of mortality in patients with coronary artery disease and heart failure. This review aimed to summarize the current evidence on the diagnostic and prognostic value of GDF-15 in different settings in cardiology.

Analysis to early warning of blood growth differentiation factor-15 in high intensity training / 中华急诊医学杂志

Objective:To explore the early warning of blood growth differentiation factor-15 (GDF15) as a new stress indicator.Methods:A total of 53 armed police soldiers selected to participate in high-intensity training, measuring the soldiers' serum GDF15, high-sensitivity C-reactive protein (S-CRP), and C-reactive protein (CRP) before and after the high-intensity training , Interleukin-6 (IL-6), Procalcitonin (PCT) levels, compare the coefficient of variation of each index; use SPSS 24 software for statistical analysis, measurement data are expressed as mean ± standard deviation (Mean±SD), The comparison of measurement data adopts group t test. Results:The GDF15 level of fighters after high-intensity training was (176.28±97.45) pg/mL, which was higher than (120.35±69.87) pg/mL before high-intensity training. The difference was very significant ( P <0.001). After high-intensity training, IL-6 and CRP levels were lower than before high-intensity training, the difference was statistically significant ( P<0.05); there was no statistically significant difference in S-CRP and PCT before and after high-intensity training ( P>0.05). The coefficient of variation of GDF15 index is smaller than S-CRP, CRP, IL-6, PCT. Conclusion:Blood growth differentiation factor-15 (GDF15) is of great significance in warning the stress state after high-intensity training. It has higher sensitivity than other conventional stress indicators like S-CRP, CRP, IL-6 and PCT.

Structural Modeling and Validation of Growth/Differentiation Factor 15 [NP_004855] Associated with Pregnancy Complication- Hyperemesis Gravidarum.

Background: Hyperemesis Gravidarum (HG) is acommon pregnancy complication that occurs in0.3–2% of pregnancies. Growth/Differentiation Factor(GDF) 15 serum levels are abnormally high in patientsassociated with HG. In silico analysis providesinformation about structure and function of GDF15.Aim and Objectives: The aim of this study was to enlistbiochemical and functional properties of GDF15protein and determine its three-dimensional structure,as GDF15 is known to be associated with risk of HG.Material and Methods: The PDB file of GDF15[NP_004855] was created by RaptorX structureprediction server. The UCLA-DOE server was used tovisual analysis of crystal structure of protein. Thevalidation for structure models was performed by usingPROCHECK. Model quality estimates were based onthe QMEAN and ProSA. Results: The model showedgood stereo-chemical property in terms of G-factorvalue -0.64, that indicates geometry of modelcorresponds to probability conformation with 95%residue in the favored region of Ramachandran plot,showing high accuracy of model prediction. The Zscore of -4.04 predicted by ProSA represents the goodquality of the model. The energy plot shows the localmodel quality by plotting knowledge-based energies asa function of amino acid sequence position.Conclusion: The generated model could be supportiveto understand the structure and functionalcharacteristics of Homo sapiens growth/differentiationfactor 15 [NP_004855]. As abnormal high serum levelsof GDF15 were observe in patients associated with HG.Therefore, the structure model of GDF15 [NP_004855]is useful to understand its role in development of HG. InSilico docking study could be explain the molecularassociation of GDF15 [NP_004855] with HG and newdrug designing, for that structure model is very useful.

GDF -15 and Severity Scores in Sickle Cell Disease Patients Attending Nnamdi Azikiwe University Teaching Hospital, Nnewi, Anambra State, Nigeria

Aim:Granulocyte differentiation factor 15 (GDF15) is a growth factor andbiomarker for many disorders where Ischaemia Reperfusion Injury (IRI) is pathophysiologically relevant. Hence theneed to evaluate GDF-15 as a biomarker inSickle Cell Disease (SCD).Study Design:This is a cross sectional study.Place and Duration of Study: Department of Haematology, Nnamdi University Teaching Hospital, Nnewi, Anambra state, Nigeria, between January and December 2018.Methods:Ninety subjects were randomly recruitedwith haemoglobin (Hb) phenotypesSS (test),AS and AA (controls); numbering30,28and 32 respectively. Disease severity was determined by calculating an objective score. 5 mls of blood was collectedandused to determine Full Blood Count (FBC),haemoglobin Phenotype andGDF-15 levels(byEnzymeLinked Immunosorbent assay).Data collected was analysed using Statistical Package for Social Sciences software version 20 (SPSS Inc., IL, Chicago, USA). P< 0.05 was considered as significant.Results: GDF-15 level was found to be significantly differentin the different HB phenotypes p= 0.005 and correlated negatively with sickle cell disease severity (r= -0.307, p= 0.098). The difference betweenmedianGDF-15 levels of HBSS subjects with mild and moderate disease was statistically significant at p= 0.01.Conclusion:We hypothesize that GDF-15 maybeapotential therapeutic target for intervention against ischaemia/reperfusion inducedmicro-vascularinjury.Natural GDF-15 mimetics maybe useful in taking advantage of this potential therapeutic target.

Growth differentiation factor 15 plays a role in predicting and monitoring the cardiotoxicity of epirubicin/cyclophosphamide-docetaxel-trastuzumab in the treatment of patients with HER-2 positive breast cancer / 实用肿瘤学杂志

Objective The aim of current study was to evaluate the effect of growth differentiation factor 15( GDF-15) on predicting and monitoring the cardiotoxicity of epirubicin/cyclophosphamide-docetaxel-trastuzumab(EC-D-T)in the treatment of HER-2 positive breast cancer patients. Methods Seventy-three patients with HER-2 positive breast cancer who received EC-D-T adjuvant therapy were enrolled. Serum levels of GDF-15,cardiac troponin I(cTnl)and amino terminal brain natriuretic peptide precursor(NT-proBNP)were measured before adjuvant therapy(M0)and after adjuvant therapy at 3 months(M3 ),6 months(M6 ),9 months(M9 ),12 months(M12 )and 15 months(M15 ). At the same time,patients underwent echocardiography at various time points to assess the left ventricular ejection fraction(LVEF). The cardiotoxicity of this study was defined as:(1)LVEF level decreased by ≥10% after treatment and the absolute value of LVEF was below 53% (normal);(2) heart failure,acute coronary syndrome or severe life-threatening heart rate abnormal. Results After initiation of EC-D-T treatment,the level of LVEF gradually decreased. Dur-ing the whole study,a total of 21(28. 8% )patients developed cardiotoxicity. At the same time,patients with cardiotoxicity had signifi-cantly higher levels of GDF-15 at M0 and cTn1 at various time points than those without cardiotoxicity. The level of ProBNP was comparable to those without cardiotoxicity. In addition,Univariate logistic regression analysis showed that baseline GDF-15 might af-fect the risk of cardiotoxicity. Multivariate logistic regression analysis showed that only cTnl level was an independent predictor for the risk of cardiotoxicity, while NT-proBNP level did not predict the risk of cardiotoxicity. Conclusion The incidence of cardiotoxicity in patients with HER-2 positive breast cancer after receiving EC-D-T is high,and GDF-15 can predict and monitor the risk of cardiotoxicity.

Effects of up regulation of GDF-15 expression on biological characteristics and PI3K/AKT signaling pathway in H9C2 cardiomyocytes induced by H2O2 / 中国免疫学杂志

Objective:To investigate the effect of up regulation of GDF-15 expression on the proliferation,apoptosis and PI3K/AKT signaling pathway of H9C2 cardiomyocytes induced by H2O2.Methods:CCK8 method was used to detect the proliferation of H9C2 cardiomyocytes treated with different concentrations of H2O2;H9C2 cells were divided into Control group,NC group,H2O2group,GDF-15+H2O2group,the cells were treated for 24 h,mRNA and protein expression of GDF-15 in each group were detected by RT-PCR and Western blot;the proliferation and apoptosis of the cells were detected by CCK8 and flow cytometry respectively;DCFH-DA probe was used to detect the level of ROS;the expression of Ki67,Bcl-2,Bax,PI3K and p-AKT protein was detected by Western blot.H9C2 cells were treated with 10 μmol/L LY294002(a PI3K/AKT signal pathway inhibitor),cell viability and apoptosis rate were detected by CCK8 assay and flow cytometryin espectively.Ki67,Bcl-2,Bax,PI3K and p-AKT protein expression were detected by Western blot.Results:Cell viability was inhibited after different concentrations H2O2treated H9C2 myocardial cells,which was concentration de-pendent (P<0.05),due to H9C2 cardiomyocytes treated with 200 μmol/L H2O2inhibited nearly half of cell proliferation,and were chosen as subjects.Compared with control group,mRNA and protein expression of GDF-15 in H2O2group were significantly increased, cell proliferation was decreased significantly,the apoptosis rate was increased,ROS level was increased,the expression of Ki67,Bcl-2, PI3K,p-AKT protein were decreased,Bax protein expression was increased(P<0.05).Compared with H2O2group,mRNA and protein expression of GDF-15 in GDF-15+H2O2group were significantly increased,cell proliferation was significantly increased,the apoptosis rate was decreased,ROS level was decreased,the expression of Ki67,Bcl-2,PI3K,p-AKT protein were increased,and Bax protein expression was decreased (P<0.05).The cell viability and protein expression of Bcl-2,PI3K and p-AKT in PI3K/AKT inhibitor group were significantly lower than those in GDF-15+H2O2group,and the apoptosis rate and Bax protein expression were significantly higher than those in GDF-15+H2O2group(P<0.05).Conclusion:Up regulation of GDF-15 expression promote the proliferation of H9C2 car-diomyocytes induced by H2O2and reduce apoptosis,and the mechanism may be related to the regulation of ROS levels,Ki67,Bcl-2,Bax expression and PI3K/AKT signaling pathway in cells.

Downregulation of GDF15 promotes proliferation of human glioblastoma cell line U87MG / 基础医学与临床

Objective To investigate the effect of growth differentiation factor 15 ( GDF15 ) downregulation on cell proliferation of human glioblastoma U 87MG cells.Methods Human glioblastoma U87MG cells with stable GDF15 downregulation was used as shGDF 15 group.U87MG cells with scramble knockdown was used as scramble group . Protein expression levels of GDF 15 were determined by Western blot analysis .Growth curve and BrdU incorporation assays were used to observe cell proliferation .Protein expression levels of ERK 1/2 and p-ERK1/2 were determined by western blot analysis .CCK-8 assays were used to observe cell proliferation .Results Compared with scramble cells, GDF15 downregulation significantly promoted cell proliferation ( P<0.05 ) , increased DNA synthesis in S phage ( P<0.01 ) , enhanced activity of ERK pathway and cell tolerance to VM-26 ( P<0.05 ) .Moreover , ERK pathway inhibitor rescued the increased cell proliferation with GDF15 downregulation.Conclusions GDF15decrease DNA synthesis in S phage and cell proliferation of human glioblastoma U 87MG cells through inhibiting ERK pathway .GDF15 is a potential target of chemotherapy sensitivity in glioblastoma clinical treatment .

Effect of sevoflurane preconditioning on serum GDF-15,TNF-α,cTnI expression during perioperative pe-riod in patients in congenital heart diseases combined with pulmonary artery hypertension / 实用医学杂志

Objective To observe the effect of sevoflurane preconditioning on serum GDF-15,TNF-α, cTnI expression during perioperative period in patients in congenital heart diseases(CHD)with pulmonary artery hypertension(PAH),and to investigate the mechanism of myocardial protection. Methods Forty adult patients of CHD with PAH who received open-heart surgery under extracorporeal circulation were randomly divided into two groups(n=20):sevoflurane preconditioning group(Group S)and the control group(Group C). In the group S, 1MAC sevoflurane was inhaled for 20 min from beginning of operation ,and followed with oxygen elution for 10 min,in twice;only inhaling pure oxygen in the Group C. The artery blood samples were collected for measurements of serum GDF-15,TNF-α,cTnI immediately before anesthesia induction(T0),at 2 h(T1),12 h(T2),24 h (T3)after aorta declamping and 7 d(T4)after operation. The restoration of spontaneous heart beat ,reperfusion arrhythmia scores,preoperative and postoperative pulmonary artery systolic pressure were recorded. Results Com-pared with preoperative pumonary artery systolic pressure(PASP),it became low in the two groups at 7 days after operation(P<0.05);compared with the group C,the rate of restoration of spontaneous heart beat was promoted, and reperfusion arrhythmia scores were decreased in the group S(P<0.05);compared with the group C,GDF-15 were increased,TNF-α,cTnI were decreased in the group S at T1～3(P < 0.05);Compared with T0,GDF-15, TNF-α,cTnI were increased in the two groups at T1～3,GDF-15 in the two groups were decreased at T4(P <0.05). Conclusion Sevoflurane preconditioning may reduce inflammatory reaction during perioperative period in patients of CHD with PAH by promoting the expression of GDF-15,inhibiting the expression of TNF-α and then improve myocardial ischemia-reperfusion injury.

Effect of sevoflurane preconditioning on serum GDF-15,TNF-α,cTnI expression during perioperative pe-riod in patients in congenital heart diseases combined with pulmonary artery hypertension / 实用医学杂志

Objective To observe the effect of sevoflurane preconditioning on serum GDF-15,TNF-α, cTnI expression during perioperative period in patients in congenital heart diseases(CHD)with pulmonary artery hypertension(PAH),and to investigate the mechanism of myocardial protection. Methods Forty adult patients of CHD with PAH who received open-heart surgery under extracorporeal circulation were randomly divided into two groups(n=20):sevoflurane preconditioning group(Group S)and the control group(Group C). In the group S, 1MAC sevoflurane was inhaled for 20 min from beginning of operation ,and followed with oxygen elution for 10 min,in twice;only inhaling pure oxygen in the Group C. The artery blood samples were collected for measurements of serum GDF-15,TNF-α,cTnI immediately before anesthesia induction(T0),at 2 h(T1),12 h(T2),24 h (T3)after aorta declamping and 7 d(T4)after operation. The restoration of spontaneous heart beat ,reperfusion arrhythmia scores,preoperative and postoperative pulmonary artery systolic pressure were recorded. Results Com-pared with preoperative pumonary artery systolic pressure(PASP),it became low in the two groups at 7 days after operation(P<0.05);compared with the group C,the rate of restoration of spontaneous heart beat was promoted, and reperfusion arrhythmia scores were decreased in the group S(P<0.05);compared with the group C,GDF-15 were increased,TNF-α,cTnI were decreased in the group S at T1～3(P < 0.05);Compared with T0,GDF-15, TNF-α,cTnI were increased in the two groups at T1～3,GDF-15 in the two groups were decreased at T4(P <0.05). Conclusion Sevoflurane preconditioning may reduce inflammatory reaction during perioperative period in patients of CHD with PAH by promoting the expression of GDF-15,inhibiting the expression of TNF-α and then improve myocardial ischemia-reperfusion injury.

Expression of GDF-15 in chronic mountain sickness rat model and discussion of the relationship with GDF-15 and hepcidin / 实用医学杂志

Objective To determine the growth differential factor 15 (GDF-15) in CMS rat model, investigate the significance of GDF-15 in CMS and the relationship between GDF-15 and hepcidin. Methods 32 rats of CMS model were taken as experimental group (EXP), the other 16 rats fed in Xining (CON) were taken as control group. The mRNA and protein expression levels of GDF-15 were detected respectively. Results Compared with that in CON group, the level of mRNA and protein of GDF-15 were significantly higher in EXP group (P<0.01). GDF-15 and EPO had correlation in EXP (r=0.397, P=0.031), but had no correlation with serum hepcidin in EXP (r = -0.224, P = 0.218). Conclusion GDF-15 can promote CMS and represent erythrocytosis, while GDF-15 has no inhibition to the expression of hepcidin.

Growth Differentiation Factor 15 Expression in Astrocytes After Excitotoxic Lesion in the Mouse Hippocampus

Growth differentiation factor 15 (GDF15) is, a member of the transforming growth factor beta (TGF-beta) superfamily of proteins. Although GDF15 is well established as a potent neurotrophic factor for neurons, little is known about its role in glial cells under neuropathological conditions. We monitored GDF15 expression in astrocyte activation after a kainic acid (KA)-induced neurodegeneration in the ICR mice hippocampus. In control, GDF15 immunoreactivity (IR) was evident in the neuronal layer of the hippocampus; however, GDF15 expression had increased in activated astrocytes throughout the hippocampal region at day 3 after the treatment with KA. LPS treatment in astrocytes dramatically increased GDF15 expression in primary astrocytes. In addition, LPS treatment resulted in the decrease of the IkappaB-alpha degradation and increase of the phosphorylation level of RelA/p65. These results indicate that GDF15 has a potential link to NF-kappaB activation, making GDF15 a valuable target for modulating inflammatory conditions.