GDF15 ameliorates sepsis-induced lung injury via AMPK-mediated inhibition of glycolysis in alveolar macrophage.

Growth differentiation factor 15 (GDF15) as a stress response cytokine is involved in the development and progression of several diseases associated with metabolic disorders. However, the regulatory role and the underlying mechanisms of GDF15 in sepsis remain poorly defined. Our study analyzed the levels of GDF15 and its correlations with the clinical prognosis of patients with sepsis. In vivo and in vitro models of sepsis were applied to elucidate the role and mechanisms of GDF15 in sepsis-associated lung injury. We observed strong correlations of plasma GDF15 levels with the levels of C-reactive protein (CRP), procalcitonin (PCT), lactate dehydrogenase (LDH), and lactate as well as Sequential Organ Failure Assessment (SOFA) scores in patients with sepsis. In the mouse model of lipopolysaccharide-induced sepsis, recombinant GDF15 inhibited the proinflammatory responses and alleviated lung tissue injury. In addition, GDF15 decreased the levels of cytokines produced by alveolar macrophages (AMs). The anti-inflammatory effect of glycolysis inhibitor 2-DG on AMs during sepsis was mediated by GDF15 via inducing the phosphorylation of the α-subunit of eukaryotic initiation factor 2 (eIF2α) and the expression of activating transcription factor 4 (ATF4). Furthermore, we explored the mechanism underlying the beneficial effects of GDF15 and found that GDF15 inhibited glycolysis and mitogen-activated protein kinases (MAPK)/nuclear factor-κB (NF-κB) signaling via promoting AMPK phosphorylation. This study demonstrated that GDF15 inhibited glycolysis and NF-κB/MAPKs signaling via activating AMP-activated protein kinase (AMPK), thereby alleviating the inflammatory responses of AMs and sepsis-associated lung injury. Our findings provided new insights into novel therapeutic strategies for treating sepsis.

GDF15 affects venous thrombosis by promoting EndMT through smad2/p-smad2 pathway.

BACKGROUND: Endothelial-to-mesenchymal transition (EndMT) is a pathophysiological change in the vascular endothelium commonly seen in the cardiovascular system. Elevated serum Growth differiention factor 15 (GDF15) has been reported in VTE patients, but the relationship and mechanism between GDF15, EndMT and VTE are still unclear. METHODS: We performed a retrospective clinical study, and human serum GDF15 expression levels were detected. The mouse DVT model was established through subtotal ligation of the mouse inferior vena cava, and then we detected intimal changes and thrombi in the stenotic inferior vena cava by haematoxylin-eosin (HE) staining, Masson staining, and Sirius Red staining. The expression levels of GDF15 and SM22 were detected by immunohistochemistry and RT‒qPCR. Serum samples of mice were collected, and the expression level of GDF15 in serum was detected. Human umbilical vein endothelial cells (HUVECs) were stimulated with a cytokine mixture (TGF-ß1 + TNF-α + IL-1ß). The role and mechanism of GDF15 in EndMT and VTE were detected in HUVECs and in a DVT mice model. RESULTS: We found that serum GDF15 levels in both VTE patients and mouse DVT models were higher than those in the control group. EndMT was increased in the stenotic vascular tissue of mice. Further experiments showed that GDF15 could promote the EndMT of HUVECs and reduce their anticoagulation and antifibrinolytic ability through the smad2/p-smad2/snail pathway. Inhibition of mature GDF15 release can significantly reduce venous thrombotic fibre deposition in mice. CONCLUSIONS: GDF15 positively promotes EndMT through activation of the Smad2/psmad2/snail pathway, and inhibition of GDF15 expression can alleviate the EndMT process, further improving the coagulation and fibrinolytic function of endothelial cells and thus reducing the local fibre deposition of venous thrombi.

Soluble Urokinase-Type Plasminogen Activator Receptor (suPAR) and Growth Differentiation Factor-15 (GDF-15) Levels Are Significantly Associated with Endothelial Injury Indices in Adult Allogeneic Hematopoietic Cell Transplantation Recipients.

Hematopoietic stem cell transplantation-associated thrombotic microangiopathy (HSCT-TMA) and graft-versus-host disease (GvHD) represent life-threatening syndromes after allogeneic hematopoietic stem cell transplantation (allo-HSCT). In both conditions, endothelial dysfunction is a common denominator, and development of relevant biomarkers is of high importance for both diagnosis and prognosis. Despite the fact that soluble urokinase plasminogen activator receptor (suPAR) and growth differentiation factor-15 (GDF-15) have been determined as endothelial injury indices in various clinical settings, their role in HSCT-related complications remains unexplored. In this context, we used immunoenzymatic methods to measure suPAR and GDF-15 levels in HSCT-TMA, acute and/or chronic GVHD, control HSCT recipients, and apparently healthy individuals of similar age and gender. We found considerably greater SuPAR and GDF-15 levels in HSCT-TMA and GVHD patients compared to allo-HSCT and healthy patients. Both GDF-15 and suPAR concentrations were linked to EASIX at day 100 and last follow-up. SuPAR was associated with creatinine and platelets at day 100 and last follow-up, while GDF-15 was associated only with platelets, suggesting that laboratory values do not drive EASIX. SuPAR, but not GDF-15, was related to soluble C5b-9 levels, a sign of increased HSCT-TMA risk. Our study shows for the first time that suPAR and GDF-15 indicate endothelial damage in allo-HSCT recipients. Rigorous validation of these biomarkers in many cohorts may provide utility for their usefulness in identifying and stratifying allo-HSCT recipients with endothelial cell impairment.

Change in Cardiac Biomarkers and Risk of Incident Heart Failure and Atrial Fibrillation in CKD: The Chronic Renal Insufficiency Cohort (CRIC) Study.

RATIONALE & OBJECTIVE: Circulating cardiac biomarkers may signal potential mechanistic pathways involved in heart failure (HF) and atrial fibrillation (AF). Single measures of circulating cardiac biomarkers are strongly associated with incident HF and AF in chronic kidney disease (CKD). We tested the associations of longitudinal changes in the N-terminal fragment of the prohormone brain natriuretic peptide (NT-proBNP), high-sensitivity troponin T (hsTnT), galectin-3, growth differentiation factor 15 (GDF-15), and soluble ST-2 (sST-2) with incident HF and AF in patients with CKD. STUDY DESIGN: Observational, case-cohort study design. SETTING & PARTICIPANTS: Adults with CKD enrolled in the Chronic Renal Insufficiency Cohort study. EXPOSURES: Biomarkers were measured at baseline and 2 years later among those without kidney failure. We created 3 categories of absolute change in each biomarker: the lowest quartile, the middle 2 quartiles, and the top quartile. OUTCOMES: The primary outcomes were incident HF and AF. ANALYTICAL APPROACH: Cox proportional hazards regression models were used to test the associations of the change categories of each cardiac biomarker with each outcome (with the middle 2 quartiles of change as the referent group), adjusting for potential confounders and baseline concentrations of each biomarker. RESULTS: The incident HF analysis included 789 participants (which included 138 incident HF cases), and the incident AF analysis included 774 participants (123 incident AF cases). In multivariable models, the top quartile of NT-proBNP change (>232pg/mL over 2years) was associated with increased risk of incident HF (HR, 1.79 [95% CI, 1.06-3.04]) and AF (HR, 2.32 [95% CI, 1.37-3.93]) compared with the referent group. Participants in the top quartile of sST2 change (>3.37ng/mL over 2years) had significantly greater risk of incident HF (HR, 1.89 [95% CI, 1.13-3.16]), whereas those in the bottom quartile (≤-3.78ng/mL over 2years) had greater risk of incident AF (HR, 2.43 [95% CI, 1.39-4.22]) compared with the 2 middle quartiles. There was no association of changes in hsTnT, galectin-3, or GDF-15 with incident HF or AF. LIMITATIONS: Observational study. CONCLUSIONS: In CKD, increases in NT-proBNP were significantly associated with greater risk of incident HF and AF, and increases in sST2 were associated with HF. Further studies should investigate whether these markers of subclinical cardiovascular disease can be modified to reduce the risk of cardiovascular disease in CKD.

Growth differentiation factor 15 (GDF-15) as potential cardiovascular risk biomarker in antiphospholipid syndrome.

OBJECTIVE: An interplay between thrombo-inflammatory and atherogenic mechanisms is recognized in cardiovascular disease (CVD) pathogenesis in APS. Herein, we examine associations of growth differentiation factor-15 (GDF-15), a pro-inflammatory cytokine identified as a potent CVD risk biomarker in the general population, with subclinical atherosclerosis in APS. METHODS: We measured plasma GDF-15 levels by an electrochemiluminescence immunoassay (cut-off 1200 pg/ml) and we examined carotid intima-media thickness (IMT) and the presence of carotid and femoral plaques using vascular ultrasound in 80 patients with APS (44 primary, 36 SLE/APS) and 40 healthy controls. We calculated the adjusted Global APS Score for cardiovascular disease (aGAPSSCVD), a revised adjusted Global APS Score (aGAPSS) for predicting CVD, including lupus anticoagulant, anticardiolipin and anti-beta2glycoprotein-I antibodies, and hypertension, dyslipidaemia, obesity, diabetes and smoking. RESULTS: GDF-15 levels were higher in APS patients vs controls, after adjusting for age and gender [absolute difference: 281 (95% CI: 141, 421) pg/ml, P < 0.001]. GDF-15 levels ≥1200 pg/ml were associated with higher mean IMT of the right and left carotid arteries [beta coefficient 0.068 (95% CI: 0.020, 0.116), P = 0.006] compared with GDF-15 levels <1200 pg/ml. GDF-15 was independently associated with mean IMT, after adjusting for gender and aGAPSSCVD [beta coefficient 0.059 (95% CI: 0.008, 0.110), P = 0.024], and additionally for statin (P = 0.025) and HCQ use (P = 0.011). GDF-15 levels ≥1200 pg/ml were associated with 2.4 times higher odds for atherosclerotic plaques (odds ratios = 2.438, 95% CI: 0.906, 6.556, P = 0.078), while this effect was reduced by including more covariates in the model. CONCLUSION: GDF-15 is independently associated with subclinical atherosclerosis in APS patients, suggesting its potential role in CVD risk stratification in APS.

The utility of growth differentiation factor-15, galectin-3, and sST2 as biomarkers for the diagnosis of heart failure with preserved ejection fraction and compared to heart failure with reduced ejection fraction: a systematic review.

The objective was to evaluate the diagnosis of heart failure with preserved ejection fraction (HFpEF) using the biomarkers, growth differentiation factor-15 (GDF-15), galectin-3 (Gal-3), and soluble ST2 (sST2), and to determine whether they can differentiate HFpEF from heart failure with reduced ejection fraction (HFrEF). Medline and Embase databases were searched with the terms diastolic heart failure or HFpEF, biomarkers, and diagnosis, limited to years 2000 to 2019. There were significantly and consistently higher levels of GDF-15, Gal-3, and sST2 in HFpEF compared to no heart failure. Importantly, the magnitude of the increase in GDF-15 or Gal-3 and possibly sST2,correlated with a greater degree of diastolic dysfunction. There were no significant differences between GDF-15, Gal-3, and sST2 in patients with HFpEF vs HFrEF. In the studies assessing these three biomarkers, BNP was significantly greater in heart failure than controls. Furthermore, BNP was significantly higher in HFrEF compared to HFpEF. The diagnostic utility of GDF-15, Gal-3, and sST2 compared to BNP was evaluated by comparing ROC curves. The data supports the contention that to distinguish HFpEF from HFrEF, an index is needed that incorporates GDF-15, Gal-3, or sST2 as well as BNP. The three biomarkers GDF-15, Gal-3, or sST2 can identify patients with HFpEF compared to individuals without heart failure but cannot differentiate HFpEF from HFrEF. BNP is higher in and is better at differentiating HFrEF from HFpEF. Indices that incorporate GDF-15, Gal-3, or sST2 as well as BNP show promise in differentiating HFpEF from HFrEF.

Modulating Properties of Piroxicam, Meloxicam and Oxicam Analogues against Macrophage-Associated Chemokines in Colorectal Cancer.

The mechanisms underlying the antineoplastic effects of oxicams have not been fully elucidated. We aimed to assess the effect of classic and novel oxicams on the expression/secretion of macrophage-associated chemokines (RTqPCR/Luminex xMAP) in colorectal adenocarcinoma cells, and on the expression of upstream the non-steroidal anti-inflammatory drug (NSAID)-activated genes NAG1, NFKBIA, MYD88, and RELA, as well as at the chemokine profiling in colorectal tumors. Meloxicam downregulated CCL4 9.9-fold, but otherwise the classic oxicams had a negligible/non-significant effect. Novel analogues with a thiazine ring substituted with arylpiperazine and benzoyl moieties significantly modulated chemokine expression to varying degree, upregulated NAG1 and NFKBIA, and downregulated MYD88. They inhibited CCL3 and CCL4, and their effect on CCL2 and CXCL2 depended on the dose and exposure. The propylene linker between thiazine and piperazine nitrogens and one arylpiperazine fluorine substituent characterized the most effective analogue. Only CCL19 and CXCL2 were not upregulated in tumors, nor was CXCL2 in tumor-adjacent tissue compared to normal mucosa. Compared to adjacent tissue, CCL4 and CXCL2 were upregulated, while CCL2, CCL8, and CCL19 were downregulated in tumors. Tumor CCL2 and CCL7 increased along with advancing T and CCL3, and CCL4 along with the N stage. The introduction of arylpiperazine and benzoyl moieties into the oxicam scaffold yields effective modulators of chemokine expression, which act by upregulating NAG1 and interfering with NF-κB signaling.

RET Receptor Tyrosine Kinase: Role in Neurodegeneration, Obesity, and Cancer.

Rearranged during transfection (RET) is the tyrosine kinase receptor that under normal circumstances interacts with ligand at the cell surface and mediates various essential roles in a variety of cellular processes such as proliferation, differentiation, survival, migration, and metabolism. RET plays a pivotal role in the development of both peripheral and central nervous systems. RET is expressed from early stages of embryogenesis and remains expressed throughout all life stages. Mutations either activating or inhibiting RET result in several aggressive diseases, namely cancer and Hirschsprung disease. However, the physiological ligand-dependent activation of RET receptor is important for the survival and maintenance of several neuronal populations, appetite, and weight gain control, thus providing an opportunity for the development of disease-modifying therapeutics against neurodegeneration and obesity. In this review, we describe the structure of RET, its signaling, and its role in both normal conditions as well as in several disorders. We highlight the differences in the signaling and outcomes of constitutive and ligand-induced RET activation. Finally, we review the data on recently developed small molecular weight RET agonists and their potential for the treatment of various diseases.

Levels of Growth Differentiation Factor 15 and Early Mortality Risk Stratification in Cardiogenic Shock.

BACKGROUND: The aim of this study was to assess the levels, kinetics, and prognostic value of growth differentiation factor 15 (GDF-15) in cardiogenic shock (CS). METHODS AND RESULTS: Levels of GDF-15 were determined in serial plasma samples (0-120 h) from 177 CS patients in the CardShock study. Kinetics of GDF-15, its association with 90-day mortality, and incremental value for risk stratification were assessed. The median GDF-150h level was 9647 ng/L (IQR 4500-19,270 ng/L) and levels above median were significantly associated with acidosis, hyperlactatemia, renal dysfunction, and higher 90-day mortality (56% vs 28%, P < .001). Serial sampling showed that non-survivors had significantly higher GDF-15 levels at all time points (P < .001 for all). Furthermore, non-survivors displayed increasing and survivors declining GDF-15 levels during the first days in CS. Higher levels of GDF-15 were independently associated with mortality. A GDF-1512h cutoff >7000 ng/L was identified as a strong predictor of death (OR 5.0; 95% CI 1.9-3.8, P = .002). Adding GDF-1512h >7000 ng/L to the CardShock risk score improved discrimination and risk stratification for 90-day mortality. CONCLUSIONS: GDF-15 levels are highly elevated in CS and associated with markers of systemic hypoperfusion and end-organ dysfunction. GDF-15 helps to discriminate survivors from non-survivors very early in CS.

Defining reference intervals for a serum growth differentiation factor-15 (GDF-15) assay in a Caucasian population and its potential utility in diabetic kidney disease (DKD).

BACKGROUND: Growth differentiation factor-15 (GDF-15), a stress responsive cytokine, is a promising biomarker of renal functional decline in diabetic kidney disease (DKD). This study aimed primarily to establish normative data and secondarily to evaluate the potential utility of GDF-15 in DKD using Roche Diagnostics electrochemiluminescence immunoassay (ECLIA) in an Irish Caucasian population. METHODS: Following informed consent, 188 healthy volunteers and 128 participants with diabetes (72 with and 56 without DKD) were recruited to a cross-sectional study. Baseline demographics, anthropometric measurements and laboratory measurements were recorded. Blood for GDF-15 measurement was collected into plain specimen tubes kept at room temperature and processed (centrifugation, separation of serum, freezing at -80 °C) within 1 h of phlebotomy pending batch analyses. Reference intervals were determined using the 2.5th and 97.5th percentiles for serum GDF-15 concentration. RESULTS: Of 188 healthy participants, 63 failed to meet study inclusion criteria. The reference interval for serum GDF-15 was 399 ng/L (90% confidence interval [CI]: 399-399) - 1335 ng/L (90% CI: 1152-1445). Receiver operator characteristics (ROC) curve analysis for DKD determined the area under the ROC curve to be 0.931 (95% CI: 0.893-0.959; p<0.001). The optimum GDF-15 cutoff for predicting DKD was >1136 ng/L providing a diagnostic sensitivity and specificity of 94.4% and 79%, respectively, and positive likelihood ratio of 4.5:1 (95% CI: 3.4-6.0). CONCLUSIONS: The reference interval for serum GDF-15 in a healthy Irish Caucasian population using Roche Diagnostics ECLIA was established and a preliminary determination of the potential of GDF-15 as a screening test for DKD was made. Further prospective validation with a larger DKD cohort will be required before the cutoff presented here is recommended for clinical use.

Association of serum growth differentiation factor 15 level with acute ischemic stroke in a Chinese population.

Background: Growth differentiation factor 15 (GDF-15) is a member of the transforming growth factor-ß family. Elevated GDF-15 concentrations are associated with increased risks of cardiovascular diseases, diabetes mellitus and cerebrovascular disease. Objective: This study aimed to determine the clinical significance of serum GDF-15 level after acute ischemic stroke (AIS) in a Chinese population. Methods: We compared serum GDF-15 levels between 83 AIS patients and 124 controls. At admission and on day 7, we recorded the National Institutes of Health Stroke Scale score and measured serum GDF-15 levels for AIS patients and for control patients at admission. Stroke volumes were calculated using diffusion-weighted magnetic resonance imaging performed at admission. Clinical outcomes were evaluated 90 days later using the modified Rankin Scale. Results: Serum GDF-15 level at admission was significantly higher in AIS patients than in controls (p < .01). GDF-15 level on day 7 was significantly higher in the poor outcomes group than in the good outcomes group (p < .05). Higher GDF-15 levels at admission and on day 7 were related to larger stroke volumes (p < .01). Binary logistic regression indicated that serum GDF-15 level at admission may be independently related with AIS (p < .01). Serum GDF-15 level on day 7 may independently associated with poor outcomes after AIS (p < .05). Conclusions: GDF-15 level at admission may independently related to AIS, and GDF-15 level on day 7 could independently predict outcomes at 90 days after AIS. GDF-15 may provide prognostic information after AIS in a Chinese population.

Effect of growth differentiation factor-15 secreted by human umbilical cord blood-derived mesenchymal stem cells on amyloid beta levels in in vitro and in vivo models of Alzheimer's disease.

Alzheimer's disease (AD), which is the most common progressive neurodegenerative disease, causes learning and memory impairment. The pathological progress of AD can derive from imbalanced homeostasis of amyloid beta (Aß) in the brain. In such cases, microglia play important roles in regulating the brain Aß levels. In the present study, we found that human umbilical cord blood-derived mesenchymal stem cells (hUCB-MSCs) can increase, through paracrine action, the ability of microglial cells to clear Aß. In order to identify the associated paracrine factors, a secretome of hUCB-MSCs co-cultured with Aß-treated BV2 microglial cells was analyzed using a human cytokine protein array. As a result, growth differentiation factor-15 (GDF-15) was identified as a predominant candidate, and its association with Aß clearance by microglial cells was investigated in vitro and in a 5XFAD mouse model. When Aß-treated BV2 cells were treated with exogenous recombinant GDF-15, the Aß levels in the culture medium decreased. Moreover, GDF-15 injection in the brain parenchyma of 5XFAD mice also led to decrease in Aß plaques. In contrast, co-culture of BV2 cells and hUCB-MSCs treated with GDF-15-specific siRNA did not influence the Aß levels in the culture medium. To elucidate how these phenomena are related, we confirmed that GDF-15 specifically increases insulin-degrading enzyme (IDE) expression in microglial cells through TGFß receptor type II (TGFßRII), both in vitro and in vivo. These findings suggest that hUCB-MSCs promote the Aß clearance ability of microglial cells through regulation of GDF-15 secretion, thus elucidating a therapeutic mechanism for AD.

GDF-15, Galectin 3, Soluble ST2, and Risk of Mortality and Cardiovascular Events in CKD.

RATIONALE & OBJECTIVE: Inflammation, cardiac remodeling, and fibrosis may explain in part the excess risk for cardiovascular disease (CVD) in patients with chronic kidney disease (CKD). Growth differentiation factor 15 (GDF-15), galectin 3 (Gal-3), and soluble ST2 (sST2) are possible biomarkers of these pathways in patients with CKD. STUDY DESIGN: Observational cohort study. SETTING & PARTICIPANTS: Individuals with CKD enrolled in either of 2 multicenter CKD cohort studies: the Seattle Kidney Study or C-PROBE (Clinical Phenotyping and Resource Biobank Study). EXPOSURES: Circulating GDF-15, Gal-3, and sST2 measured at baseline. OUTCOMES: Primary outcome was all-cause mortality. Secondary outcomes included hospitalization for physician-adjudicated heart failure and the atherosclerotic CVD events of myocardial infarction and cerebrovascular accident. ANALYTIC APPROACH: Cox proportional hazards models used to test the association of each biomarker with each outcome, adjusting for demographics, CVD risk factors, and kidney function. RESULTS: Among 883 participants, mean estimated glomerular filtration rate was 49±19mL/min/1.73m2. Higher GDF-15 (adjusted HR [aHR] per 1-SD higher, 1.87; 95% CI, 1.53-2.29), Gal-3 (aHR per 1-SD higher, 1.51; 95% CI, 1.36-1.78), and sST2 (aHR per 1-SD higher, 1.36; 95% CI, 1.17-1.58) concentrations were significantly associated with mortality. Only GDF-15 level was also associated with heart failure events (HR per 1-SD higher, 1.56; 95% CI, 1.12-2.16). There were no detectable associations between GDF-15, Gal-3, or sST2 concentrations and atherosclerotic CVD events. LIMITATIONS: Event rates for heart failure and atherosclerotic CVD were low. CONCLUSIONS: Adults with CKD and higher circulating GDF-15, Gal-3, and sST2 concentrations experienced greater mortality. Elevated GDF-15 concentration was also associated with an increased rate of heart failure. Further work is needed to elucidate the mechanisms linking these circulating biomarkers with CVD in patients with CKD.

Induction of Growth Differentiation Factor 15 in Skeletal Muscle of Old Taurine Transporter Knockout Mouse.

It has been identified that skeletal muscle is an endocrine tissue. Since skeletal muscle aging affects not only to muscle strength and function but to systemic aging and lifespan, myokines secreted from skeletal muscle may be crucial factors for intertissue communication during aging. In the present study, we investigated the expression of myokines associated with skeletal muscle aging in taurine transporter knockout (TauTKO) mice, which exhibit the accelerated skeletal muscle aging. Among transforming growth factor (TGF)-beta family genes, only growth and differentiation factor 15 (GDF15) was markedly higher (>3-fold) in skeletal muscle of old TauTKO mice compared with that of either young TauTKO mice or old wild-type mice. Circulating levels of GDF15 were also elevated in old TauTKO mice. An elevation in circulating GDF15 was also observed in very old (30-month-old) wild-type mice, while skeletal GDF15 levels were normal. The treatment of cultured mouse C2C12 myotubular cells with aging-related factors that mediate cellular stresses, such as oxidative stress (hydrogen peroxide) and endoplasmic reticulum stress (tunicamycin and thapsigargin), leads to an increase in GDF15 secretion. In conclusion, GDF15 is a myokine secreted by aging-related stress and may control aging phenotype.

Oral Treatment with the Ghrelin Receptor Agonist HM01 Attenuates Cachexia in Mice Bearing Colon-26 (C26) Tumors.

The gastrointestinal hormone ghrelin reduces energy expenditure and stimulates food intake. Ghrelin analogs are a possible treatment against cancer anorexia-cachexia syndrome (CACS). This study aimed to investigate whether oral treatment with the non-peptidergic ghrelin receptor agonist HM01 counteracts CACS in colon-26 (C26) tumor-bearing mice. The C26 tumor model is characterized by pronounced body weight (BW) loss and muscle wasting in the absence of severe anorexia. We analyzed the time course of BW loss, body composition, muscle mass, bone mineral density, and the cytokines interleukin-6 (IL-6) and macrophage-inhibitory cytokine-1 (MIC-1). Moreover, we measured the expression of the muscle degradation markers muscle RING-finger-protein-1 (MuRF-1) and muscle atrophy F-box (MAFbx). After tumor inoculation, MIC-1 levels increased earlier than IL-6 and both cytokines were elevated before MuRF-1/MAFbx expression increased. Oral HM01 treatment increased BW, fat mass, and neuronal hypothalamic activity in healthy mice. In tumor-bearing mice, HM01 increased food intake, BW, fat mass, muscle mass, and bone mineral density while it decreased energy expenditure. These effects appeared to be independent of IL-6, MIC-1, MuRF-1 or MAFbx, which were not affected by HM01. Therefore, HM01 counteracts cachectic body weight loss under inflammatory conditions and is a promising compound for the treatment of cancer cachexia in the absence of severe anorexia.

Risk stratification using growth differentiation factor 15 in patients undergoing transcatheter aortic valve implantation.

AIMS: Growth differentiation factor 15 (GDF15) shows potential predictive value in various cardiac conditions. We investigated relationships between GDF15 and clinical or procedural outcomes in patients with severe aortic stenosis undergoing transcatheter aortic valve implantation (TAVI) in order to propose clinically useful predictive risk stratification model. METHODS: This prospective single-center registry enrolled 88 consecutive patients with severe symptomatic aortic stenosis treated with TAVI. Clinical parameters were collected and biomarkers including GDF-15 were measured within 24 h before TAVI. All relevant clinical outcomes according to the Valve Academic Research Consortium-2 were collected over the follow-up period. RESULTS: The cohort included 52.3% of females. The mean age of study participants was 81 years; the mean Society of Thoracic Surgeons (STS) score and logistic EuroSCORE were 3.6% and 15.4%, respectively. The mortality over the entire follow-up period was 10.2%; no death was observed within the first 30 days following TAVI. Univariate analysis showed significant associations between GDF15 and mortality (P=0.0006), bleeding (P=0.0416) and acute kidney injury (P=0.0399). A standard multivariate logistic regression model showed GDF-15 as the only significant predictor of mortality (P=0.003); the odds ratio corresponding to an increase in GDF15 of 1000 pg/mL was 1.22. However, incremental predictive value was not observed when the STS score was combined with GDF15 in this predictive model. CONCLUSIONS: Based on our observations, preprocedural elevated GDF15 levels are associated with increased mortality and demonstrate their additional value in predicting adverse clinical outcomes in a TAVI population.

Correlation between serum GDF-15 level and pulmonary vascular morphological changes and prognosis in patients with pulmonary arterial hypertension.

Objective: To investigate how serum GDF-15 concentration affects pulmonary artery hemodynamics and pulmonary vascular morphological changes in patients with pulmonary arterial hypertension. Methods: A total of 45 patients admitted to our hospital from December 2017 to December 2019, were selected for the study. Pulmonary vascular hemodynamics and pulmonary vascular morphology were detected by RHC and IVUS. Serum GDF-15 levels were detected by enzyme-linked immunosorbent assay (ELISA). Based on the concentration of GDF-15, the patients were divided into two groups-the normal GDF-15 group (GDF-15 <1,200 pg/ml, 12 cases) and the elevated GDF-15 group (GDF-15 ≥1,200 pg/ml, 33 cases). A statistical analysis was performed to compare the effects of normal blood GDF-15 levels and high serum GDF-15 levels on hemodynamics and pulmonary vascular morphology in each group of patients. Results: The average levels of RVP, sPAP, dPAP, mPAP, and PVR in patients with elevated GDF-15 levels were higher than those in patients with normal GDF-15 levels. The difference between the two groups was statistically significant (P < 0.05). The average levels of Vd, elastic modulus, stiffness index ß, lesion length, and PAV in the normal GDF-15 group were lower than those in the elevated GDF-15 group. The average levels of compliance, distensibility, and minimum l umen area were higher than those in the elevated GDF-15 group. The difference between the two groups was statistically significant (P < 0.05). The survival analysis results showed that the 1-year survival rate of patients with normal GDF-15 levels and elevated GDF-15 levels was 100% and 87.9%, respectively, and that the 3-year survival rate of patients with normal GDF-15 levels and elevated GDF-15 levels was 91.7% and 78.8%, respectively. The survival rates of the two groups were compared by the Kaplan Meier method, and the difference was not statistically significant (P > 0.05). Conclusion: Patients with pulmonary arterial hypertension with elevated GDF-15 levels have higher pulmonary arterial pressure, higher pulmonary vascular resistance, and more serious pulmonary vascular lesions, which are potentially more harmful. There was no statistically significant difference in survival rates among patients with different serum GDF-15 levels.

Growth differentiation factor 15 (GDF-15) in endocrinology.

Human growth differentiation factor 15 (GDF-15) is a widely distributed protein that has shown to play multiple roles in both physiological and pathological conditions. In healthy individuals, GDF-15 is mainly expressed in the placenta, followed by the prostate, although low levels of expression have also been detected in different organs. GDF-15 acts through a recently identified receptor called glial-derived neurotrophic factor (GDNF) receptor alpha-like (GFRAL) which signals through the rearranged during transfection (RET) tyrosine kinase receptor. The effects of GDF-15 are pleiotropic and include appetite regulation, and actions on metabolism, pregnancy, cell survival, immune response, and inflammation. GDF-15 also plays different roles in the pathophysiology of cardiovascular disease, autoimmunity, cancer-associated anorexia/cachexia, and diabetes. In recent years, several studies have reported a link between GDF-15 and the endocrine system. In this review, we up-date and summarize the relevant investigations of the relationships between GDF-15 and different endocrine conditions. We also assess the potential pathogenic role and potential therapeutic applications of GDF-15 in the field of endocrinology.

​Meta-analysis of the applied value of the growth differentiation factor 15 detection in HFpEF diagnosis.

OBJECTIVE: To systematically evaluate the diagnostic value of growth differentiation factor-15 (GDF-15) for heart failure with preserved ejection fraction (HFpEF). METHODS: Chinese and English literature on the diagnosis of HFpEF using GDF-15 were searched in PubMed, Embase, Web of Science (WOS), Cochrane Library, China National Knowledge Infrastructure (CNKI), China Science and Technology Journal Database, WanFang Database, and others. The literature on the diagnostic value of the GDF-15 test for HFpEF was screened from the establishment of the database to April 2023 according to the inclusion and exclusion criteria. The quality of the included studies was then assessed based on the QUADAS-2 list, and the threshold effect was evaluated using the Meta-Disc1.4 software. STATA 17.0 software was used to combine the sensitivity, specificity, and area under the curve (AUC) of the included studies. Moreover, heterogeneity was evaluated by the inconsistency index (I2) and Cochrane Q index, and the source of heterogeneity was explored by subgroup analysis, meta-regression, and sensitivity analysis. Finally, Deek's quantitative funnel plot was used to assess whether there was publication bias among the included studies. RESULTS: A total of ten studies involving 1550 patients were included. The pooled sensitivity was 0.77 (95%CI: 0.70-0.83), the specificity was 0.79 (95%CI: 0.68-0.87), the positive likelihood ratio was 3.9 (95%CI: 2.6-5.9), and the negative likelihood ratio was 0.21 (95%CI:0.12-0.36). The diagnostic odds ratio was 19 (95%CI: 9-37), and the AUC of SROC was 0.88 (95%CI: 0.85-0.9). The results of the heterogeneity test showed significant heterogeneity among the studies (I2 = 96%, p = 0.000 < 0.01). Meta-regression analysis showed that there was a significant difference in diagnostic efficacy between the gold standard group (p = 0.0064 < 0.05), while there was no significant difference in diagnostic efficacy among the three subgroups of age, gender, and comprehensive group (p > 0.05). After excluding the articles that did not include biomarkers for the diagnosis of HFpEF, the average age ≥73 years old, and the proportion of women >55%, the remaining four articles had the pooled sensitivity of 0.80 (I2 = 60.1%, p = 0.06 >​ 0.05) and the pooled specificity of 0.84 (I2 = 0%, p = 0.61 >​0.05), which insisted that there is no significant heterogeneity among them. CONCLUSION: With its high sensitivity and specificity for HFpEF diagnosis, GDF-15 is a novel biomarker for HFpEF diagnosis.

GDF15 Is an Eribulin Response Biomarker also Required for Survival of DTP Breast Cancer Cells.

Drug tolerant persister (DTP) cells enter into a reversible slow-cycling state after drug treatment. We performed proteomic characterization of the breast cancer (BC) DTP cell secretome after eribulin treatment. We showed that the growth differentiation factor 15 (GDF15) is a protein significantly over-secreted upon eribulin treatment. The biomarker potential of GDF15 was confirmed in 3D-cell culture models using BC cells lines and PDXs, as well as in a TNBC in vivo model. We also found that GDF15 is required for survival of DTP cells. Direct participation of GDF15 and its receptor GFRAL in eribulin-induction of DTPs was established by the enhanced cell killing of DTPs by eribulin seen under GDF15 and GFRAL loss of function assays. Finally, we showed that combination therapy of eribulin plus an anti-GDF15 antibody kills BC-DTP cells. Our results suggest that targeting GDF15 may help eradicate DTP cells and block the onset of acquired resistance.