Relationship between serum GDF-15,chemerin,PTX3 levels and obesity,insulin resistance and inflammation in patients with type 2 diabetes mellitus and the construction and evaluation of their predictive efficacy / 国际检验医学杂志

Objective To explore the relationship between serum growth differentiation factor-15(GDF-15),chemerin,pentraxin 3(PTX3)levels and obesity,insulin resistance and inflammatory factors in patients with type 2 diabetes mellitus(T2DM),and to construct and evaluate the predictive efficacy.Methods A total of 231 T2DM patients admitted to the hospital from February 2020 to September 2022 were selected as T2DM group.Another 100 healthy subjects who came to the hospital for physical examination during the same period were selected as the control group.Serum GDF-15,chemerin and PTX3 levels of the two groups were detected and compared by enzyme-linked immunosorbent assay(ELISA).Clinical data of the two groups were collected and compared.Pearson correlation analysis and multiple linear regression were used to analyze the relationship between serum GDF-15,chemerin,PTX3 levels and obesity,insulin resistance and inflammation.Multivariate Logistic regression was used to evaluate the independent risk factors for T2DM development,and the com-bined prediction model of serum GDF-15,chemerin and PTX3 was constructed,and receiver operating charac-teristic(ROC)curve was plotted to evaluate its predictive efficacy for T2DM development.Results Compared with the control group,body mass index(BMI),waist-to-hip ratio(WHR),systolic blood pressure,total cho-lesterol,triglyceride,fasting blood glucose,fasting insulin(FINS),homeostasis model assessment of insulin re-sistance(HOMA-1R),interleukin(IL)-1β,IL-6,GDF-15,chemerin and PTX3 were all increased in T2DM group,and the differences were statistically significant(P＜0.05).Pearson correlation analysis showed that se-rum GDF-15,chemerin and PTX3 levels were positively correlated with BMI,WHR,FINS,HOMA-IR,IL-1βand IL-6 in T2DM group(P＜0.05).Multiple linear regression analysis showed that BMI,FINS,HOMA-IR,IL-1β and IL-6 were positively correlated with serum GDF-15,chemerin and PTX3 levels(P＜0.05).Multiva-riate Logistic regression analysis showed that the increase of serum GDF-15,chemerin and PTX3 levels was an independent risk factor for T2DM development(P＜0.05).ROC curve analysis results showed that the com-bined prediction model of serum GDF-15,chemerin and PTX3 had better prediction efficiency,and its area un-der the curve,sensitivity,specificity and accuracy were higher than those applied alone.Conclusion The levels of GDF-15,chemerin and PTX3 in serum of T2DM patients are elevated,and their levels increase with the ex-acerbation of obesity,insulin resistance and inflammatory response in T2DM patients.The combined predic-tion model constructed in this study has good predictive efficacy and has high predictive value for the occur-rence of T2DM.

Expression and diagnostic value of growth differentiation factor 15 in patients with septic cardiomyopathy / 中华危重病急救医学

Objective:To explore the expression of growth differentiation factor 15 (GDF15) in patients with septic cardiomyopathy and its value in the diagnosis of septic cardiomyopathy.Methods:A observational study was conducted. Fifty patients with septic cardiomyopathy admitted to Shanxi Bethune Hospital from May 2022 to March 2023 were selected as the experimental group. Forty-six patients with acute coronary syndrome (ACS) in the same period were selected as the case control group. Forty-nine healthy adults were selected as the healthy control group, who underwent physical examination in the physical examination center during the same period. The demographic data and clinical indicators of the subjects were recorded, and the serum GDF15 level was detected by double sandwich enzyme-linked immunosorbent assay (ELISA). And the 28-day outcome of patients with septic cardiomyopathy was followed up, and they were divided into survival group and death group. The serum GDF15 level of subjects in each group and its correlation with clinical indicators were analyzed and compared. Binary Logistic regression was used to analyze the risk factors of septic cardiomyopathy. Receiver operator characteristic curve (ROC curve) was used to evaluate the value of GDF15 in the diagnosis of septic cardiomyopathy.Results:The serum GDF15 level of experimental group was significantly higher than that in the case control group and healthy control group [ng/L: 314.14 (221.96, 469.56) vs. 39.08 (26.27, 76.85), 6.39 (3.35, 14.42), both P < 0.01]. Correlation analysis showed that serum GDF15 level in patients with septic cardiomyopathy were correlated with cardiac troponin I (cTnI, r = 0.295, P = 0.038), brain natriuretic peptide (BNP, r = 0.464, P = 0.009), sequential organ failure assessment (SOFA, r = 0.363, P = 0.010) and acute physiology and chronic health evaluation Ⅱ (APACHEⅡ, r = 0.316, P = 0.025). However, there was no significant correlation with white blood cell count, neutrophil count, lymphocyte count, procalcitonin, C-reactive protein, lactic acid, albumin and other clinical indicators ( r values were 0.086, 0.123, -0.051, 0.055, 0.119, 0.199, -0.234, all P > 0.05). Serum GDF15 level, SOFA score and APACHEⅡ score in the death group (30 cases) were significantly higher than those in the survival group [20 cases; GDF15 (ng/L): 382.93±159.61 vs. 289.66±158.46, SOFA: 10.00 (7.00, 12.00) vs. 6.00 (5.00, 9.50), APACHEⅡ: 21.70±6.07 vs. 14.85±7.57, all P < 0.05]. Binary Logistic regression analysis showed that serum GDF15 was an independent risk factor for the onset of septic cardiomyopathy [odds ratio ( OR) = 1.062, 95% confidence interval (95% CI) was 1.011-1.115, P = 0.016]. ROC curve showed that the area under the curve (AUC) of GDF15 for predicting septic cardiomyopathy was 0.971, the specificity was 100%, and the sensitivity was 90.3%. Conclusion:The serum GDF15 level of patients with septic cardiomyopathy is significantly increased, and GDF15 may be used as an effective biomarker for the early diagnosis of septic cardiomyopathy.

Effects of early standardized enteral nutrition on preventing acute muscle loss in the acute exacerbation of chronic obstructive pulmonary disease patients with mechanical ventilation / 世界急诊医学杂志（英文）

@#BACKGROUND: To investigate the effects of early standardized enteral nutrition (EN) on the cross-sectional area of erector spine muscle (ESMcsa), plasma growth differentiation factor-15 (GDF-15), and 28-day mortality of acute exacerbation of chronic obstructive pulmonary disease (AECOPD) patients with invasive mechanical ventilation (MV). METHODS: A total of 97 AECOPD patients with invasive MV were screened in the ICUs of the First People's Hospital of Lianyungang. The conventional EN group (stage I) and early standardized EN group (stage II) included 46 and 51 patients, respectively. ESMcsa loss and GDF-15 levels on days 1 and 7 of ICU admission and 28-day survival rates were analyzed. RESULTS: On day 7, the ESMcsa of the early standardized EN group was significantly higher than that of the conventional EN group, while the plasma GDF-15 levels were significantly lower than those in the conventional EN group (ESMcsa: 28.426±6.130 cm2 vs. 25.205±6.127 cm2; GDF-15: 1661.608±558.820 pg/mL vs. 2541.000±634.845 pg/mL; all P<0.001]. The 28-day survival rates of the patients in the early standardized EN group and conventional EN group were 80.40% and 73.90%, respectively (P=0.406). CONCLUSION: ESMcsa loss in AECOPD patients with MV was correlated with GDF-15 levels, both of which indicated acute muscular atrophy and skeletal muscle dysfunction. Early standardized EN may prevent acute muscle loss and intensive care unit-acquired weakness (ICU-AW) in AECOPD patients.

Associations between serum GDF15 and glycolipid metabolism disorder in metabolic associated fatty liver patients / 中华内科杂志

Objective:To investigate relationships between serum growth differentiation factor 15 (GDF15) and glycolipid metabolism in patients with metabolic associated fatty liver disease (MAFLD).Methods:The current investigation was a cross-sectional study. A total of 333 patients from the Fengxian District Central Hospital were recruited into the study after physical examination from February 2020 to February 2021. There were 107 patients with MAFLD and type 2 diabetes mellitus (T2DM), including 54 males and 53 females with a mean age of (57±11) years. There were 65 patients with simple MAFLD only, including 32 men and 33 women with a mean age of (49±5) years. There were 105 patients with T2DM only, including 53 men and 52 women, with a mean age of (56±10) years. A control group of 56 people without MAFLD or diabetes,28 male, 28 female, mean age (48±6) years, was also included in the study. Serum GDF15 was measured via enzyme-linked immunosorbent assays. IBM SPSS 26.0 was used for statistical analysis. Logistic regression was used to evaluate relationships between GDF15 and metabolic abnormalities in MAFLD patients.Results:GDF15 progressively increased in the control [385 (296, 484) ng/L], nonobese MAFLD [388 (319, 435) ng/L], obese MAFLD [426 (354, 527) ng/L], T2DM [664 (483, 900) ng/L], and MAFLD+T2DM groups [770 (560, 1 074) ng/L]( H=113.82, P=0.001). There was no significant difference in serum GDF15 between the simple MAFLD [406 (339, 524) ng/L] and control group ( U=1 505.50, P=0.132). GDF15 was significantly higher in the MAFLD+T2DM group than in the T2DM-only group ( U=4 573.50, P=0.019). In logistic regression analysis increased GDF15 was associated with increased risks of simple MAFLD [odds ratio ( OR)=2.202], T2DM ( OR=29.656), and MAFLD+T2DM( OR=58.197). In patients with MAFLD, serum GDF15 was higher in the FIB4 index>1.45 group [773 (534, 1 162) ng/L] than in the FIB4 index<1.45 group [527 (389, 787) ng/L] ( U=1 709.50, P<0.001). Increased GDF15 was associated with an increased risk of advanced liver fibrosis ( OR=2.388). Conclusion:In patients with simple MAFLD, GDF15 level was not significantly higher than in the control group. In the T2DM-only group and the MAFLD+T2DM group GDF15 was significantly higher than in the control group. Increased serum GDF15 was associated with increased risk and severity of MAFLD complicated with abnormal glucose and lipid metabolism. High GDF15 increased the risk of advanced fibrosis in MAFLD patients.

Correlation of serum growth differentiation factor-15 with coronary slow flow phenomenon and atherosclerosis / 中华老年心脑血管病杂志

Objective To investigate the correlation of serum growth differentiation factor-15(GDF-15)with coronary slow flow phenomenon(CSFP)and coronary atherosclerosis(AS).Meth-ods A total of 190 patients undergoing first-time coronary angiography in our hospital from January 2019 to June 2022 were recruited,and then according to definite diagnosis,divided into CSFP group(n=60),AS group(n=70)and NC group(normal coronary flow,n=60).Their gen-eral data,risk factors for coronary heart disease,clinical biochemical indexes and electrocardio-gram were collected.The serum GDF15 level was measured by ELISA.Results Age(OR=1.065,95％CI:1.014-1.119,P=0.021),smoking history(OR=0.330,95％CI:0.132-0.823,P=0.001)and GDF-15(OR=1.006,95％CI:1.003-1.009,P=0.018)were independent influencing factors of AS.Age(OR=0.956,95％CI:0.926-0.988,P=0.024)and GDF-15(OR=1.003,95％CI:1.000-1.006,P=0.031)were independent influencing factors of CSFP.The GDF-15 level was significantly higher in the moderate or severe AS group than the CSFP group and the mild AS group(867.02±222.82 ng/L vs 568.21±163.03 ng/L and 635.41±214.95 ng/L,P＜0.01).Serum GDF-15 level was positively correlated with hs-CRP level(r=0.228,P=0.014).Conclusion GDF-15 is highly expressed in the patients with CSFP and with AS.With the increase of GDF-15 level,the severe the degree of AS gradually.GDF-15 is highly correlated with hs-CRP.

Association between peripheral blood growth differentiation factor 15 deoxyribonucleic acid methylation and sarcopenia among the elderly / 中华老年医学杂志

Objective:To examine the relationship between sarcopenia and DNA methylation in the promoter of the growth differentiation factor 15(GDF15)gene in elderly individuals.Methods:This cross-sectional study collected data from 865 elderly individuals aged 65 years and above who underwent physical examination at the Yuetang Town Community Medical Center in Yangzhou City between May and September 2020.The verification set included 431 males and 434 females with an age range of 65-100 years and a mean age of(76.0±5.9)years.The diagnosis of sarcopenia was based on the consensus diagnostic criteria of the Asian Sarcopenia Working Group in 2019.The study included 295 cases in the non-sarcopenia group and 470 cases in the sarcopenia group.The study selected 50 non-sarcopenia patients and 50 age-gender matched sarcopenia patients as the explore set for DNA methylation sequencing of the GDF15 gene.The sequencing results were then verified using the methylation-specific polymerase chain(PCR)method in the verification center.Additionally, serum GDF15 levels were detected using the enzyme-linked immunosoradsorption method.The study analyzed the correlation between GDF15 methylation levels, serum GDF15 levels, and sarcopenia.Results:The study found that individuals with sarcopenia had lower levels of body mass index(BMI), appendicular skeletal muscle mass(ASMI), grip strength, and gait speed in both the discovery and validation sets compared to those without sarcopenia( P<0.05). Additionally, the DNA methylation of GDF15 was found to be lower in the sarcopenic group compared to the non-sarcopenic group[93.7%(79.6%, 98.0%) vs.97.7%(95.3%, 99.0%), Z=-9.294, P<0.01]. The results of the correlation analysis indicate a positive relationship between the methylation level and appendicular skeletal muscle mass( r=0.206, P<0.01), grip strength( r=0.297, P<0.01), and gait speed( r=0.383, P<0.01). Conversely, there was a negative correlation between the methylation level and serum GDF15 level( r=-0.249, P<0.05). The study conducted ROC analysis to determine the predictive ability of GDF15 methylation for sarcopenia found that the area under the curve was 0.700 with a cut-off score of 92.7%.Furthermore, binary regression analysis revealed that low GDF15 methylation( OR=1.136, 95% CI: 1.098~1.175, P<0.01)was linked to a higher risk of sarcopenia, even after adjusting for age, sex, and BMI.The serum GDF15 level was higher in the sarcopenic group compared to the non-sarcopenic group[(0.665±0.432)pg/L vs.(0.465±0.211)pg/L( t=-2.452, P<0.05)]. Additionally, it was observed that the methylation of GDF15 was negatively correlated with the serum GDF15 level( r=-0.249, P<0.05). Conclusions:A low level of GDF15 methylation has been found to be linked with a higher risk of sarcopenia, suggesting that measuring GDF15 methylation could potentially serve as a biomarker for diagnosing sarcopenia.

Prognostic value of growth differentiation factor 15 and hepatocyte growth factor in 5-year mortality for patients with chronic heart failure / 中华老年医学杂志

Objective:To evaluate the value of growth differentiation factor 15(GDF-15)and hepatocyte growth factor(HGF)in mortality prediction for patients with chronic heart failure(CHF)during a 5-year follow-up.Methods:This prospective case-control study enrolled 141 CHF patients hospitalized at the First Affiliated Hospital of Anhui Medical University between August 2015 and September 2017, including 59 with preserved ejection fraction(HFpEF)and 82 with non-preserved ejection fraction(non-HFpEF). Using all-cause mortality as the endpoint during the 60-month follow-up, there were 93 cases in the survival group and 48 cases in the death group.Clinical baseline data of patients in the two groups were compared, and the prognostic value of GDF-15 and HGF for CHF was assessed using multivariate logistic regression analysis, receiver operating characteristic curves(ROC curves), the area under the ROC curve(AUC), and Kaplan-Meier survival curves.Results:The results of multivariate Logistic regression analysis showed that GDF-15, HGF, glomerular filtration rate, and body mass index were independent risk factors for CHF prognosis during the 60-month follow-up; The degrees of predictive ability on mortality in 60-months in patients with heart failure were estimated for GDF-15( AUC=0.769, 95% CI: 0.685-0.854), HGF( AUC=0.765, 95% CI: 0.676 to 0.854), body mass index( AUC=0.689, 95% CI: 0.594 to 0.783), and glomerular filtration rate( AUC=0.612, 95% CI: 0.518 to 0.705). The AUC values of GDF-15 and HGF were greater than those of the body mass index and the glomerular filtration rate.Using GDF-15=2 326 ng/L and HGF=1, 603 ng/L as the cut-off values, the Kaplan-Meier survival curves showed statistically significant differences in survival rates between the two groups( P<0.05)The mortality rate in the non-HFpEF group was higher when GDF15 ≥2, 326 ng/L and HGF ≥1, 603 ng/L(100%, 15/15)than that in the HFpEF group(50%, 2/4), and the difference was statistically significant( χ2=5.526, P<0.05). Conclusions:GDF-15, HGF, the estimated glomerular filtration rate and the body mass index are independent prognostic risk factors for CHF during a 60-month follow-up period.GDF-15 and HGF are independent predictors of all-cause death in patients with CHF, especially those with non-HFpEF during 5-years.

Serum miR-1976 and GDF-15 levels and associations with postural and gait abnormalities in patients with Parkinson disease / 中风与神经疾病杂志

@#Objective To investigate the changes in the levels of serum miR-1976 and growth differentiation factor 15(GDF-15) in patients with Parkinson disease(PD) and their relationships with postural and gait abnormalities. Methods We included 76 patients with PD(PD group) and 53 healthy participants from health examination(control group) in our hospital from March 2020 to October 2022.Serum miR-1976 and GDF-15 levels were measured for all the subjects. The expression of serum miR-1976 and GDF-15 was compared between PD patients with different motor subtypes. A receiver operating characteristic(ROC) curve was used to analyze the value of miR-1976 combined with GDF-15 in predicting PD with the type of abnormal posture and gait. Results Serum miR-1976 and GDF-15 levels in the PD group were significantly higher than those in the control group(both P<0.05). Spearman correlation analysis showed that the severity of PD was positively correlated with serum miR-1976 and GDF-15 levels(both P<0.05). Logistic regression analysis showed that high expression of serum miR-1976 and GDF-15 was related to posture/gait abnormality type in patients with PD(both P<0.05). The ROC curve showed that the area under the curve for miR-1976 plus GDF-15 was 0.907,which was largest,with sensitivity of 92.50% and specificity of 77.78%. Conclusion Serum miR-1976 and GDF-15 levels were increased in patients with PD,positively reflecting the severity of the disease. In addition,the patients with posture/gait abnormality type had higher serum miR-1976 and GDF-15 levels than those with tremor type. Combined detection can effectively predict PD with posture/gait abnormality type,which can improve the diagnostic accuracy and facilitate early clinical prevention and treatment.

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 of the diagnostic and prognostic value of growth differentiation factor 15 and procalcitonin in sepsis / 中华检验医学杂志

Objective:To investigate the diagnostic and prognostic value of the growth differentiation factor 15 (GDF15) and the procalcitonin (PCT) in sepsis.Methods:A total number of 137 patients with sepsis (considered as the sepsis group) and 59 patients with inflammatory infection but not diagnosed as sepsis (the non-sepsis group) received treatment in intensive care unit of Renming Hospital of Wuhan University were collected from July 2020 to January 2021, and 62 cases of healthy physical examination (control group) were simultaneously chosen as control. Sepsis patients were divided into two groups (death group [ n=48] and survival group [ n=89]) according to their 28-day′s survival. The serum levels of GDF15, PCT, C-reactive protein (CRP), interleukin-6 (IL-6) and interleukin-10 (IL-10) were examined, and the levels of each index, was dynamically monitored on the 1st, 3rd and 7th day after admission. The differences of the two indicators between different groups were compared by non-parametric test. The correlation between GDF15 and PCT was analyzed by Spearman correlation test. The receiver operating characteristic (ROC) curve was drawn to evaluate the diagnostic and prognostic value of the two indicators for sepsis. Results:The levels of GDF15 in the sepsis group, non-sepsis group and control group were 3.22 (1.39, 6.31) μg/L, 0.84 (0.21, 1.66) μg/L and 0.11 (0.09, 0.13) μg/L, respectively. The levels of PCT were 13.10 (1.99, 50.25) μg/L, 0.24 (0.13, 0.68) μg/L and 0.05 (0.03, 0.10) μg/L, respectively. The levels of CRP were 115.80 (26.40, 184.07) mg/L, 24.20 (11.30, 53.20) mg/L and 0.50 (0.50, 2.76) mg/L, respectively. The levels of IL-6 were 68.26 (21.59, 255.46) ng/L, 33.20 (10.81, 89.27) ng/L and 8.82 (7.33, 11.23) ng/L, respectively. The levels of IL-10 were 11.30 (5.88, 25.50) ng/L, 9.34 (5.65, 16.90) ng/L and 4.94 (4.31, 5.31) ng/L, respectively. The GDF15, PCT, CRP and IL-6 of the sepsis group were significantly higher than those of the non-sepsis group (The U values were 67.681, 86.034, 44.164 and 38.934, respectively, with P values less than 0.05) and the control group (The U values were 136.475, 138.667, 120.701 and 100.886, respectively, with P values less than 0.001). There was no significant difference in IL-10 between sepsis group and nonsepsis group, but it was higher than that of control group ( U=80.221, P<0.001). There was a positive correlation between GDF15 and PCT in patients with sepsis, and the spearman correlation coefficient was 0.234 ( P=0.006). The GDF15 of the death group and the survival group were 5.49 (3.60, 8.25) μg/L and 2.03 (1.06, 3.69) μg/L, and the PCT levels were 26.45 (11.23, 94.25) μg/L and 9.08 (1.33, 22.75) μg/L, respectively. GDF15 and PCT in the death group were significantly higher than those in the survival group ( U values were 3 305.500 and 3 060.000, respectively, and P values were both less than 0.001). The GDF15 and PCT levels in the death group were higher than those in the survival group on the 1st, 3rd and 7th day of dynamic monitoring ( P<0.05), however, the level of CRP and IL-10 were not significantly different ( P>0.05). The level of IL-6 in the death group was not significantly different from that of the death group on 1st day, but was higher than that of the survival group on the 3rd and 7th day ( P<0.05). The area under the curve (AUC) of GDF15, PCT, CRP, IL-6 and IL-10 alone and in the combined diagnosis of sepsis were 0.899, 0.938, 0.874, 0.789, 0.698 and 0.962, respectively. The combined detection of AUC was better than a single index; the GDF15, PCT, CRP, IL-6 and IL-10 alone and combined detection of sepsis prognosis AUC were 0.774, 0.716, 0.522, 0.623, 0.520 and 0.839, respectively, the combined detection of AUC is also better than single index. Conclusions:GDF15 and PCT have good clinical reference value in the differential diagnosis and prognosis of sepsis. The combination of indicators has a higher clinical value. GDF15 may become a biomarker for the diagnosis and prognosis of sepsis.

Growth Differentiation Factor-15 Produces Analgesia by Inhibiting Tetrodotoxin-Resistant Nav1.8 Sodium Channel Activity in Rat Primary Sensory Neurons / 神经科学通报·英文版

Growth differentiation factor 15 (GDF-15) is a member of the transforming growth factor-β superfamily. 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.

The Signaling Pathway of Growth Differentiation Factor 15 and Its Receptor GFRAL / 中国生物化学与分子生物学报

Growth differentiation factor 15 (GDF15), a member of the transforming growth factor β (TGF-β) superfamily, is a new class of dimeric polypeptides with very low homology with other TGF-β family members. GDF15 was originally found in activated macrophages where it was secreted into the body circulation in two different cellular pathways. Moreover, GDF15 as a stress protein is widely involved in many signal pathways such as phosphoinositide 3-kinase / protein kinase B, extracellular signal-regulated kinase, c-Jun N-terminal kinase and nuclear factor-κB, and so on, and thus involved in the regulation of various disease processes. In addition, GDF15 as a new type of stress molecule acts as a biomarker and plays a regulatory role in obesity, weight loss, cancer development, cardiovascular disease, inflammation and autoimmune diseases. Glial-derived neurotrophic factor receptor alpha-like (GFRAL) is the specific receptor of GDF15, and the molecular basis of its activity is to conduct signal transduction through GFRAL-dependent binding into multimers. The intervention of the GDF15-GFRAL signaling pathway has a great application potential in the development of weight-loss drugs and cancer prognosis recovery drugs. This review focuses on the recent progress of GDF15-GFRAL and its related signaling pathways, the molecular structure of GDF15 and GFRAL, and the mechanism of GDF15-GFRAL signaling pathway, which reveals the role and regulatory ability of GDF15 as a biomarker in the development of disease and provides new insights in potential and treatment strategies of regulating the GDF15-GFRAL signaling pathway in related diseases.

The Correlation between GDF15 and sudden death / 中华急诊医学杂志

Objective:To explore the early warning and prediction value of GDF15 for sudden death patients.Methods:From January to December 2018, 49 patients with sudden death who were treated in the Emergency Department of the First Clinical Center of PLA General Hospital were included in the case group, and 46 healthy physical examiners in the Physical Examination Center of the Hospital were randomly selected as the control group. The general situation, comparison of myocardial markers and analysis of the basic data of the case group were carried out, so as to evaluate the early warning value of each myocardial marker in sudden death.Results:Patients aged 40-49 years old accounted the highest proportion among sudden death cases, reaching 26.54%. Sudden death under 60 years old accounted for 59.19%, and the ratio of male to female was 3.83:1. There were significant differences between the case group and the control group in CK-MB [(41.35±98.38) vs. (3.13±2.17), P=0.009], CK [(2652.82±6845.66) vs. (102.73±47.93), P=0.012], and GDF15 [(549.80±809.79) vs. (115.70±167.42), P=0.001]. At the same time, the AUC value of GDF15 was 0.816, which has the highest diagnostic value for sudden death. And CK-MB, CK and GDF15 had no correlation with age. Conclusions:GDF15, as a biological marker, has a good early warning function in sudden death.

The value of growth differentiation factor 15 in early diagnosis of acute chest pain / 中华急诊医学杂志

Objective:To explore the value of growth differentiation factor 15 (GDF15) in the early diagnosis of acute chest pain.Methods:A total of 96 patients with acute chest pain admitted to the Emergency Department of Hainan Hospital of PLA General Hospital from January to November 2020 were retrospectively collected. The sex, age, troponin T, creatine kinase, creatine kinase isoenzyme, GDF15 and B-type natriuretic peptide of patients within 30 min after admission were recorded, and the differences of each index in different groups were compared. ROC curve was drawn to evaluate the diagnostic value of GDF15 and TNT/BNP in acute coronary syndrome (ACS). The Gensini score, left ventricular ejection fraction, length of stay in hospital and the number of stents were calculated, and the correlation between these indexes and GDF15 concentration was evaluated.Results:The general trend of acute chest pain was more male than female (72.92% vs. 27.08%) , the oldest group was the UA group (64.67 ± 13.87) years old , the youngest group was cardiac arrest group (47.29 ± 9.99) years old . There were higher rates of hypertension in the STEMI group, NSTEMI group and UA group, and none of the groups showed significant advantage in diabetes. The GDF15 concentration was higher in ACS related chest pain group [(2.360 ± 1.710) ng/mL vs. (1.380 ± 1.040) ng/mL, P<0.01]. The area under the Receiver Operating Characteristic Curve (AUC) of GDF15 combined with TNT was up to 0.863. GDF15 concentration was negatively correlated with ejection fraction, positively correlated with Gensini score, positively correlated with the number of stents implanted, and positively correlated with the length of hospital stay. Conclusions:GDF15 is valuable in the diagnosis and prognosis of acute chest pain. The combination of GDF15 and TNT can improve the diagnostic rate of ACS.

Growth Differentiation Factor-15 Produces Analgesia by Inhibiting Tetrodotoxin-Resistant Nav1.8 Sodium Channel Activity in Rat Primary Sensory Neurons / 神经科学通报·英文版

Growth differentiation factor 15 (GDF-15) is a member of the transforming growth factor-β superfamily. 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.

Protective effect of Shuxuening Injection on brain tissue of rats with acute cerebral infarction and its mechanism / 吉林大学学报(医学版)

Objective: To investigate the|protective effect of Shuxuening Injection on the brain tissue of the rats with acute cerebral infarction, and to elucidate its mechanism. Methods: Fifty rats were randomly divided into control group, sham operation group, model group, nimodipine group and Shuxuening Injection group ( n=10). The rat models of acute cerebral infarction were made by internal carotid artery suture method in model group, nimodipine group and Shuxuening Injection group. The common carotid arteries, the external carotid arteries and the internal carotid arteries of the rats in sham operation group were separated∗ and only the external carotid arteries were ligated; the rats in control group were not treated with operation; the rats in Shuxuening Injection group were given Shuxuening Injection, the rats in nimodipine group were given nimodipine∗ and the rats in control group, model group and sham operation group were given normal saline at the same volume. The score of neurological impairment, water contents in brain tissue and relative cerebral infarction areas of the rats in various groups were measured. HE staining was used to observe the morphology of brain tissue of the rats in various groups, and immumohistochemical staining was used to detect the expression levels of growth differentiation factor-15 (GDF-15) and C-reactive protein (CRP) in brain tissue of the rats in various groups. EL ISA method was used to detect the levels of tumor necrosis factor-a (TNF-a), interleukin-6 (IL-6) and interleukin-1(3 (1L-1|3) in brain tissue of the rats in various groups. Results: The cortical structures of cortex of the rats in control group and sham operation group were complete and the cells were arranged neatly; the cytoplasm and nucleus of the nerve cells of the rats in model group were wrinkled, and the interstitium between nerve cells and capillaries were loose; the swelling degrees of cerebral cortical nerve cells and glial cells and the loose degrees of stroma of the rats in Shuxuening Injection group were reduced, and the histopathological manifestations were similar to those in nimodipine group. Compared with control group and sham operation group∗ the water content in brain tissue of the rats in model group was significantly increased ( P 0.05). Conclusion: Shuxuening Injection can protect the acute cerebral infarction by up-regulating the expression of GDF-15 and inhibiting the expression of CRP in brain tissue of the rats with acute cerebral infarction, reducing the levels of inflammatory cytokines and improving the neurological function.

Relationship between plasma ACTA,BNP,GDF－15 and IL－6 levels and heart failure / 中国基层医药

Objective To investigate the relationship between plasma activin A (ACTA),B－type natriuretic peptide(BNP),growth differentiation factor －15 (GDF－15) and interleukin－6 ( IL－6) levels and heart failure. Methods From January 2017 to December 2018,80 patients with acute heart failure admitted to Lishui Central Hospitalwere selected as observation group.According to NYHA cardiac function classification , 23 patients were classified as grade II,30 patients were classified as grade Ⅲand 27 patients were classified as grade Ⅳ.Another 60 healthy people were selected as control group from January 2017 to December 2018.The left ventricular end －diastolic diameter(LVEDD) and left ventricular ejection fraction (LVEF) were measured by Doppler echocardiography ,and the levels of ACTA, BNP, GDF －15 and IL －6 were measured by ELISA.Results The plasma ACTA [(2.43 ± 0.54)ng／mL],BNP[(219.31 ±34.25)ng／L],GDF－15[(854.31 ±46.57)ng／L],IL－6[(183.25 ±39.89)ng／L] in the observation group were significantly higher than those in the control group [(0.32 ±0.10) ng／mL,(16.74 ± 3.89)ng／L,(467.52 ±60.91)ng／L,(40.31 ±6.57) ng／L]( t＝29.859,45.553,42.591,27.455,all P＜0.05). The LVEDD[(65.73 ±5.38) mm] in the observation group was higher than that in the control group [(47.83 ± 4.31)mm],while the LVEF[(39.82 ±3.56)%]was lower than that in the control group [(64.32 ±4.16)%]( t＝21.170,37.475,all P＜0.05).The ACTA [(3.98 ±0.58) ng／mL],BNP[(304.21 ±41.30) ng／L],GDF－15 [(989.83 ±50.38) ng／L],IL－6[(249.81 ±45.61) ng／L] in grad Ⅳ group were lower than those in grade Ⅱgroup[(1.17 ±0.21)ng／mL,(135.42 ±23.98)ng／L,(735.24 ±41.87)ng／L,(120.74 ±33.45)ng／L] and gradeⅢgroup[(2.41 ±0.52)ng／mL,(217.27 ±35.46)ng／L,(861.32 ±53.46) ng／L,(185.42 ±42.31) ng／L] ( F＝8.391,23.154,17.849,14.568,all P＜0.05).The plasma levels of ACTA,BNP,GDF－15 and IL－6 in gradeⅢgroup were lower than those in gradeⅡgroup (t＝10.764,9.517,9.322,6.025,all P＜0.05).The LVEDD[(72.31 ± 5.91) mm] in grade Ⅳ group was higher than that in grade Ⅱ group [(58.98 ±4.64) mm] and grade Ⅲ group [(66.01 ±5.48) mm], and the LVEF [( 29.97 ±3.36)%] was lower than that in grade Ⅱ group [(51.54 ± 3.27)%]and gradeⅢgroup[(40.35 ±3.81)%],the differences were statistically significant (F＝12.415,9.829, all P＜0.05).The LVEDD in grade Ⅲgroup was higher than that in grade Ⅱgroup,and the LVEF was lower than that in gradeⅡgroup,the differences were statistically significant ( t ＝4.176,10.856,all P＜0.05).Conclusion The levels of ACTA,BNP,GDF－15 and IL－6 in plasma are increased in patients with acute heart failure ,and are closely related to the progress of the disease.They can be used as diagnostic and prognostic indicators of acute heart failure.

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 / 中华医学杂志(英文版)

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.

Relationship between plasma ACTA, BNP, GDF-15 and IL-6 levels and heart failure / 中国基层医药

Objective@#To investigate the relationship between plasma activin A(ACTA), B-type natriuretic peptide(BNP), growth differentiation factor-15 (GDF-15) and interleukin-6 (IL-6) levels and heart failure.@*Methods@#From January 2017 to December 2018, 80 patients with acute heart failure admitted to Lishui Central Hospital were selected as observation group.According to NYHA cardiac function classification, 23 patients were classified as grade II, 30 patients were classified as grade Ⅲ and 27 patients were classified as grade Ⅳ.Another 60 healthy people were selected as control group from January 2017 to December 2018.The left ventricular end-diastolic diameter(LVEDD) and left ventricular ejection fraction(LVEF) were measured by Doppler echocardiography, and the levels of ACTA, BNP, GDF-15 and IL-6 were measured by ELISA.@*Results@#The plasma ACTA[(2.43±0.54)ng/mL], BNP[(219.31±34.25)ng/L], GDF-15[(854.31±46.57)ng/L], IL-6[(183.25±39.89)ng/L]in the observation group were significantly higher than those in the control group[(0.32±0.10)ng/mL, (16.74±3.89)ng/L, (467.52±60.91)ng/L, (40.31±6.57)ng/L](t=29.859, 45.553, 42.591, 27.455, all P<0.05). The LVEDD[(65.73±5.38)mm] in the observation group was higher than that in the control group[(47.83±4.31)mm], while the LVEF[(39.82±3.56)%]was lower than that in the control group[(64.32±4.16)%](t=21.170, 37.475, all P<0.05). The ACTA[(3.98±0.58)ng/mL], BNP[(304.21±41.30)ng/L], GDF-15[(989.83±50.38)ng/L], IL-6[(249.81±45.61)ng/L] in grad Ⅳ group were lower than those in grade Ⅱ group[(1.17±0.21)ng/mL, (135.42±23.98)ng/L, (735.24±41.87)ng/L, (120.74±33.45)ng/L] and grade Ⅲ group[(2.41±0.52)ng/mL, (217.27±35.46)ng/L, (861.32±53.46)ng/L, (185.42±42.31)ng/L](F=8.391, 23.154, 17.849, 14.568, all P<0.05). The plasma levels of ACTA, BNP, GDF-15 and IL-6 in gradeⅢgroup were lower than those in grade Ⅱ group (t=10.764, 9.517, 9.322, 6.025, all P<0.05). The LVEDD[(72.31±5.91)mm]in grade Ⅳ group was higher than that in grade Ⅱ group[(58.98±4.64)mm]and grade Ⅲ group[(66.01±5.48)mm], and the LVEF[(29.97±3.36)%]was lower than that in grade Ⅱ group[(51.54±3.27)%]and grade Ⅲ group[(40.35±3.81)%], the differences were statistically significant (F=12.415, 9.829, all P<0.05). The LVEDD in grade Ⅲ group was higher than that in grade Ⅱ group, and the LVEF was lower than that in gradeⅡgroup, the differences were statistically significant(t=4.176, 10.856, all P<0.05).@*Conclusion@#The levels of ACTA, BNP, GDF-15 and IL-6 in plasma are increased in patients with acute heart failure, and are closely related to the progress of the disease.They can be used as diagnostic and prognostic indicators of acute heart failure.

Effect of nerve growth factor on expression level of growth differentiation factor-15 in brain tissue of rats with cerebral infarction / 吉林大学学报(医学版)

Objective: To investigate the effect of nerve growth factor (NGF) on the expression level of growth differentiation factor-15 (GDF-15) in the brain tissue of the rats with cerebral infarction, and to elucidate the mechanism of NGF in the rats with cerebral infarction. Methods: The middle cerebral artery occlusion (MCAO) models were established by the Longa' s method. A total of 54 SD rats were randomly divided into sham operation group, model group and NGF group, and there were 18 rats in each group. The rats in NGF group were given NGF (50 μg middot; kg-1) by intraperitoneal injection, and equal volume of normal saline was given to the rats in sham operation (the artery was isolated without ligation) group and model group. The neurological function scores of the rats in various groups were measured 1, 3 and 7 d after operation; HE staining was used to observe the pathomorphology of nerves in brain tissue and immunohistochemical staining was used to detect the number of GDF-15 positive cells; the expression levels of GDF-15 in brain tissue of the rats in various groups were detected by ELISA method. Results: The results of HE staining showed that the degrees nerve cell necrosis, interstitial edema and glial cell proliferation were relatively low in NGF group 7 d after operation. Compared with sham operation group, the neurological function scores, the number of GDF-15 positive cells, and the expression levels of GDF-15 in brain tissue of the rats in model group and NGF group were significantly increased (P<0. 05). Compared with model group, the neurological function scores of the rats in NGF group were significantly decreased 3 and 7 d after operation (P<0. 05), and the number of GDF-15 positive cells and the expression levels of GDF-15 in brain tissue of the rats in NGF group were significantly increased at different time points after operation (P<0. 05). Conclusion: NGF can protect the brain nerve by up-regulating the expression level of GDF-15 in brain tissue and improving the nerve function.