Growth differentiation factor-15 and incident chronic kidney disease: a population-based cohort study.

BACKGROUND: The relationship between growth differentiation factor 15 (GDF-15) and the development of chronic kidney disease (CKD) is still unclear. We sought to examine whether plasma GDF-15 was related to incident CKD and kidney function decline using a large prospective cohort study. METHODS: 4318 participants of the Malmö Diet and Cancer Study-Cardiovascular Cohort were examined in 1991-1994. Incidence of CKD was followed prospectively by linkage with national patient registers. Estimated glomerular filtration rate (eGFR) was available for all participants at baseline, and was re-measured in a subgroup of 2744 subjects after 16.6 ± 1.49 years. Incidence of CKD was examined in relation to GDF-15 using Cox regression analysis. Logistic regression was used to examine the association of GDF-15 with eGFR change and eGFR-based CKD. Models were carefully corrected for potential confounders including baseline eGFR, N-terminal pro-B-type natriuretic peptide, and competing risk from death. RESULTS: 165 patients developed CKD after 19.2 ± 4.04 years of follow-up. The adjusted hazard ratio (95% confidence interval, CI) for CKD in 4th versus 1st quartile of GDF-15 was 2.37 (1.33, 4.24) (p for trend < 0.01). Each per 1 standard deviation increase in GDF-15 was associated with a decline in eGFR of - 0.97 mL/min/1.73 m2 (95% CI, - 1.49 ~ - 0.45; p < 0.001). GDF-15 was also significantly associated eGFR-based CKD in 2713 subjects with baseline eGFR ≥60 mL/min/1.73 m2. CONCLUSIONS: GDF-15 predicted incidence of CKD and eGFR decline in the general population, independent of a wide range of potential risk factors and competing risk of death.

Transcriptional Regulation of GDF15 by EGR1 Promotes Head and Neck Cancer Progression through a Positive Feedback Loop.

Growth and differentiation factor 15 (GDF15), a divergent member of the transforming growth factor-ß (TGF-ß) superfamily, has been reported to be overexpressed in different kinds of cancer types. However, the function and mechanism of GDF15 in head and neck cancer (HNC) remains unclear. The Cancer Genome Atlas (TCGA) data show that the expression of GDF15 is significantly associated with tumor AJCC stage, lymph vascular invasion and tumor grade in HNC. In this study, we confirmed that knockdown of GDF15 attenuated: cell proliferation, migration and invasion via regulation of EMT through a canonical pathway; SMAD2/3 and noncanonical pathways; PI3K/AKT and MEK/ERK in HNC cell lines. Furthermore, we found that early growth response 1 (EGR1) was a transcription factor of GDF15. Interestingly, we also demonstrated that GDF15 could regulate the expression of EGR1, which meant a positive feedback loop occurred between these two factors. Moreover, combined inhibition of both GDF15 and EGR1 in a HNC mouse xenograft model showed significantly decreased tumor volume compared to inhibition of EGR1 or GDF15 alone. Our study showed that the GDF15-EGR1 signaling axis may be a good target in HNC patients.

The clinical impact of growth differentiation factor-15 in heart disease: A 2019 update.

Growth differentiation factor-15 (GDF-15), also known as macrophage inhibitory cytokine-1 (MIC-1) or non-steroidal anti-inflammatory drug-activated gene (NAG-1) has been identified as a biomarker of response to treatment and prognosis in cardiovascular diseases. GDF-15 is a member of the transforming growth factor-ß superfamily and is involved in several pathological conditions such as inflammation, cancer, cardiovascular, pulmonary and renal diseases. Cardiac myocytes produce and secrete GDF-15 in response to oxidative stress, stimulation with angiotensin II or proinflammatory cytokines, ischemia, and mechanical stretch. Other cellular sources of GDF-15 production are macrophages, vascular smooth muscle cells, endothelial cells, and adipocytes, which secrete GDF-15 in response to oxidative or metabolic stress or stimulation of proinflammatory cytokines. GDF-15 is induced in hypertrophic and dilated cardiomyopathy after volume overload, ischemia, and heart failure. GDF-15 can be used as a marker of prognosis in patients with cardiovascular disorders, in combination with conventional prognostic factors, such as N-terminal pro B-type natriuretic peptide (NT-proBNP) and high-sensitivity troponin T (hs-TnT).

Relationship between GDF15 level and bone metabolism in postmenopausal Chinese women.

Background: Growth differentiation factor 15 (GDF15), is a newly identified member of the transforming growth factor-beta (TGF-ß) family. It circulates as a 24.5-kDa homodimer. However, the function of GDF15 in bone metabolism remains unclear. In this study, we investigated the function of GDF15 in postmenopausal Chinese women.Methods: We measured serum GDF15 levels, bone mineral density (BMD), and bone turnover markers in 201 postmenopausal Chinese women ranging in age from 47 to 80 years.Results: The concentration of serum GDF15 increased with age. Growth differentiation factor 15 levels displayed a negative correlation with lumbar spine, femoral neck, and total hip BMD. After adjusting for age, this association still existed and was significant. We identified age, GDF15, body mass index (BMI), and estradiol to be associated with BMD. Furthermore, we found that GDF15 levels had a significant negative relationship with bone alkaline phosphatase (BAP) levels; this relationship remained significant after adjustment. However, there was no significant correlation between levels of GDF15 and N-terminal telopeptide of type I collagen (NTX).Conclusions: For postmenopausal Chinese women, GDF15 is a negative predictor of BMD and has a negative correlation with bone formation biomarker BAP. In other words, GDF15 exerts negative regulation on bone mass by inhibiting bone formation.

The Predictive Value of Growth Differentiation Factor-15 in Recurrence of Atrial Fibrillation after Catheter Ablation.

The mechanisms underlying the recurrence of atrial fibrillation (AF) after radiofrequency catheter ablation (RFCA) are not well concerned. The study sought to explore the association between growth differentiation factor-15 (GDF-15) and the incidence of recurrent events among AF patients after the ablation procedure. We prospectively included 150 consecutive AF patients who underwent RFCA. Clinical information about the patients was collected. Blood samples on the second morning of hospital admission and three months after RFCA were collected, and enzyme-linked immunosorbent assay (ELISA) was used to measure the concentration of GDF-15. All participants were followed up at specific times (1st/3rd/6th/12th/18th/24th months) after RFCA to record recurrences events. During a median follow-up of 14.0 months, AF recurrence occurred in 37(24.7%) patients. Baseline serum GDF-15 level in the persistent AF group was significantly higher than the paroxysmal AF group [1140(854~1701)ng/L vs. 1062(651~1374)ng/L, P = 0.039]. Baseline serum GDF-15 level in the recurrence group was significantly higher than the nonrecurrence group [1287(889~1768) ng/L vs. 1062(694~1373)ng/L, P = 0.022]. Serum GDF-15 level at three months after RFCA was significantly lower than the baseline [870 (579~1270) ng/L vs. 1155 (735~1632)ng/L, P < 0.001]. The baseline GDF-15 correlated significantly with LAP (r = 0.296, P < 0.001) and LAAV(r = -0.235, P = 0.003). Kaplan-Meier analysis showed a significantly lower event-free survival time in the high baseline GDF-15 (≥1287.3 ng/L) group than the low baseline GDF-15 (<1287.3 ng/L) group (17.1 months vs. 20.4 months, Log Rank P = 0.017). In the multivariate Cox regression, baseline GDF-15(HR 1.053, 95% CI 1.007-1.100, P = 0.022) and LAD (HR 1.124, 95% CI 1.011-1.250, P = 0.030) were independent predictors of AF recurrence after RFCA. Our study indicated increased preprocedural GDF-15 is associated with left atrial remodeling and acts as a predictor of AF recurrence after ablation.

Growth Differentiation Factor-15 and Risk of CKD Progression.

Growth differentiation factor-15 (GDF-15) is a member of the TGF-ß cytokine superfamily that is widely expressed and may be induced in response to tissue injury. Elevations in GDF-15 may identify a novel pathway involved in loss of kidney function among patients with CKD. Among participants in the Clinical Phenotyping and Resource Biobank (C-PROBE) study and the Seattle Kidney Study (SKS), we tested whether kidney tissue expression of GDF15 mRNA correlates with circulating levels of GDF-15 and whether elevations in circulating GDF-15 are associated with decline in kidney function. In matching samples of 24 patients with CKD from the C-PROBE study, circulating GDF-15 levels significantly correlated with intrarenal GDF15 transcript levels (r=0.54, P=0.01). Among the 224 C-PROBE and 297 SKS participants, 72 (32.1%) and 94 (32.0%) patients, respectively, reached a composite end point of 30% decline in eGFR or progression to ESRD over a median of 1.8 and 2.0 years of follow up, respectively. In multivariable models, after adjusting for potential confounders, every doubling of GDF-15 level associated with a 72% higher (95% confidence interval, 1.21 to 4.45; P=0.003) and 65% higher (95% confidence interval, 1.08 to 2.50; P=0.02) risk of progression of kidney disease in C-PROBE and SKS participants, respectively. These results show that circulating GDF-15 levels strongly correlated with intrarenal expression of GDF15 and significantly associated with increased risk of CKD progression in two independent cohorts. Circulating GDF-15 may be a marker for intrarenal GDF15-related signaling pathways associated with CKD and CKD progression.

GDF15 regulates Kv2.1-mediated outward K+ current through the Akt/mTOR signalling pathway in rat cerebellar granule cells.

GDF15 (growth/differentiation factor 15), a novel member of the TGFß (transforming growth factor ß) superfamily, plays critical roles in the central and peripheral nervous systems, but the signal transduction pathways and receptor subtypes involved are not well understood. In the present paper, we report that GDF15 specifically increases the IK (delayed-rectifier outward K+ current) in rat CGNs (cerebellar granule neurons) in time- and concentration-dependent manners. The GDF15-induced amplification of the IK is mediated by the increased expression and reduced lysosome-dependent degradation of the Kv2.1 protein, the main α-subunit of the IK channel. Exposure of CGNs to GDF15 markedly induced the phosphorylation of ERK (extracellular-signal-regulated kinase), Akt and mTOR (mammalian target of rapamycin), but the GDF15-induced IK densities and increased expression of Kv2.1 were attenuated only by Akt and mTOR, and not ERK, inhibitors. Pharmacological inhibition of the Src-mediated phosphorylation of TGFßR2 (TGFß receptor 2), not TGFßR1, abrogated the effect of GDF15 on IK amplification and Kv2.1 induction. Immunoprecipitation assays showed that GDF15 increased the tyrosine phosphorylation of TGFßRII in the CGN lysate. The results of the present study reveal a novel regulation of Kv2.1 by GDF15 mediated through the TGFßRII-activated Akt/mTOR pathway, which is a previously uncharacterized Smad-independent mechanism of GDF15 signalling.

Growth differentiation factor-15 induces expression of ATP-binding cassette transporter A1 through PI3-K/PKCζ/SP1 pathway in THP-1 macrophages.

OBJECTIVE: The aim of this study was to determine whether ATP-binding cassette transporter A1 (ABCA1) was up-regulated by growth differentiation factor-15 (GDF-15) via the phosphoinositide 3-kinase (PI3K)/protein kinase Cζ (PKCζ)/specificity protein 1 (SP1) pathway in THP-1 macrophages. METHODS AND RESULTS: We investigated the effects of different concentrations of GDF-15 on ABCA1 expression in THP-1 macrophages. The results showed that GDF-15 dramatically increased cholesterol efflux and decreased cellular cholesterol levels. In addition, GDF15 increased ABCA1 mRNA and protein levels. The effects of GDF-15 on ABCA1 protein expression and cellular cholesterol efflux were abolished by wither inhibition or depletion of PI3K, PKCζ and SP1, respectively, suggesting the potential roles of PI3K, PKCζ and SP1 in ABCA1 expression. Taken together, GDF-15 appears to activate PI3K, PKCζ and SP1 cascade, and then increase ABCA1 expression, thereby promoting cholesterol efflux and reducing foam cell formation. CONCLUSION: Our results suggest that GDF-15 has an overall protective effect on the progression of atherosclerosis, likely through inducing ABCA1 expression via the PI3K/PKCζ/SP1 signaling pathway and enhancing cholesterol efflux.

Obesity, inflammation, and lung injury (OILI): the good.

Obesity becomes pandemic, predisposing these individuals to great risk for lung injury. In this review, we focused on the anti-inflammatories and addressed the following aspects: adipocytokines and obesity, inflammation and other mechanisms, adipocytokines and lung injury in obesity bridged by inflammation, and potential therapeutic targets. To sum up, the majority of evidence supported that adiponectin, omentin, and secreted frizzled-related protein 5 (SFRP5) were reduced significantly in obesity, which is associated with increased inflammation, indicated by increase of TNF α and IL-6, through activation of toll-like receptor (TLR4) and nuclear factor light chain κ B (NF- κ B) signaling pathways. Administration of these adipocytokines promotes weight loss and reduces inflammation. Zinc-α 2-glycoprotein (ZAG), vaspin, IL-10, interleukin-1 receptor antagonist (IL-1RA), transforming growth factor ß (TGF-ß1), and growth differentiation factor 15 (GDF15) are also regarded as anti-inflammatories. There were controversial reports. Furthermore, there is a huge lack of studies for obesity related lung injury. The effects of adiponectin on lung transplantation, asthma, chronic obstructive pulmonary diseases (COPD), and pneumonia were anti-inflammatory and protective in lung injury. Administration of IL-10 agonist reduces mortality of acute lung injury in rabbits with acute necrotizing pancreatitis, possibly through inhibiting proinflammation and strengthening host immunity. Very limited information is available for other adipocytokines.

Growth differentiation factor-15 (GDF-15) suppresses in vitro angiogenesis through a novel interaction with connective tissue growth factor (CCN2).

Growth differentiation factor-15 (GDF-15) and the CCN family member, connective tissue growth factor (CCN2), are associated with cardiac disease, inflammation, and cancer. The precise role and signaling mechanism for these factors in normal and diseased tissues remains elusive. Here we demonstrate an interaction between GDF-15 and CCN2 using yeast two-hybrid assays and have mapped the domain of interaction to the von Willebrand factor type C domain of CCN2. Biochemical pull down assays using secreted GDF-15 and His-tagged CCN2 produced in PC-3 prostate cancer cells confirmed a direct interaction between these proteins. To investigate the functional consequences of this interaction, in vitro angiogenesis assays were performed. We demonstrate that GDF-15 blocks CCN2-mediated tube formation in human umbilical vein endothelial (HUVEC) cells. To examine the molecular mechanism whereby GDF-15 inhibits CCN2-mediated angiogenesis, activation of αV ß3 integrins and focal adhesion kinase (FAK) was examined. CCN2-mediated FAK activation was inhibited by GDF-15 and was accompanied by a decrease in αV ß3 integrin clustering in HUVEC cells. These results demonstrate, for the first time, a novel signaling pathway for GDF-15 through interaction with the matricellular signaling molecule CCN2. Furthermore, antagonism of CCN2 mediated angiogenesis by GDF-15 may provide insight into the functional role of GDF-15 in disease states.

Growth differentiation factor 15 in heart failure: an update.

Growth differentiation factor 15 (GDF-15) is a stress-responsive cytokine expressed in the cardiovascular system. GDF-15 is emerging as a biomarker of cardiometabolic risk and disease burden. GDF-15 integrates information from cardiac and extracardiac disease pathways that are linked to the incidence, progression, and prognosis of heart failure (HF). Increased circulating levels of GDF-15 are associated with an increased risk of developing HF in apparently healthy individuals from the community. After an acute coronary syndrome, elevated levels of GDF-15 are indicative of an increased risk of developing adverse left ventricular remodeling and HF. In patients with established HF, the levels of GDF-15 and increases in GDF-15 over time are associated with adverse outcomes. The information provided by GDF-15 is independent of established risk factors and cardiac biomarkers, including BNP. More studies are needed to elucidate how the information provided by GDF-15 can be used for patient monitoring and formulating treatment decisions. Further understanding of the pathobiology of GDF-15 may lead to the discovery of new treatment targets in HF.

Growth differentiation factor-15 prevents glucotoxicity and connexin-36 downregulation in pancreatic beta-cells.

Pancreatic beta cell dysfunction is a hallmark of type 2 diabetes. Growth differentiation factor 15 (GDF15), which is an energy homeostasis regulator, has been shown to improve several metabolic parameters in the context of diabetes. However, its effects on pancreatic beta-cell remain to be identified. We, therefore, performed experiments using cell models and histological sectioning of wild-type and knock-out GDF15 mice to determine the effect of GDF15 on insulin secretion and cell viability. A bioinformatics analysis was performed to identify GDF15-correlated genes. GDF15 prevents glucotoxicity-mediated altered glucose-stimulated insulin secretion (GSIS) and connexin-36 downregulation. Inhibition of endogenous GDF15 reduced GSIS in cultured mouse beta-cells under standard conditions while it had no impact on GSIS in cells exposed to glucolipotoxicity, which is a diabetogenic condition. Furthermore, this inhibition exacerbated glucolipotoxicity-reduced cell survival. This suggests that endogenous GDF15 in beta-cell is required for cell survival but not GSIS in the context of glucolipotoxicity.

Identification of TWSG1 as a second novel erythroid regulator of hepcidin expression in murine and human cells.

In thalassemia and other iron loading anemias, ineffective erythropoiesis and erythroid signaling molecules are thought to cause inappropriate suppression of a small peptide produced by hepatocytes named hepcidin. Previously, it was reported that the erythrokine GDF15 is expressed at very high levels in thalassemia and suppresses hepcidin expression. In this study, erythroblast expression of a second molecule named twisted gastrulation (TWSG1) was explored as a potential erythroid regulator of hepcidin. Transcriptome analyses suggest TWSG1 is produced during the earlier stages of erythropoiesis. Hepcidin suppression assays demonstrated inhibition by TWSG1 as measured by quantitative polymerase chain reaction (PCR) in dosed assays (1-1000 ng/mL TWSG1). In human cells, TWSG1 suppressed hepcidin indirectly by inhibiting the signaling effects and associated hepcidin up-regulation by bone morphogenic proteins 2 and 4 (BMP2/BMP4). In murine hepatocytes, hepcidin expression was inhibited by murine Twsg1 in the absence of additional BMP. In vivo studies of Twsg1 expression were performed in healthy and thalassemic mice. Twsg1 expression was significantly increased in the spleen, bone marrow, and liver of the thalassemic animals. These data demonstrate that twisted gastrulation protein interferes with BMP-mediated hepcidin expression and may act with GDF15 to dysregulate iron homeostasis in thalassemia syndromes.

Growth Factors and Their Roles in Multiple Sclerosis Risk.

Background: Previous studies have suggested essential roles of growth factors on the risk of Multiple Sclerosis (MS), but it remains undefined whether the effects are causal. Objective: We applied Mendelian randomization (MR) approaches to disentangle the causal relationship between genetically predicted circulating levels of growth factors and the risk of MS. Methods: Genetic instrumental variables for fibroblast growth factor (FGF) 23, growth differentiation factor 15 (GDF15), insulin growth factor 1 (IGF1), insulin-like growth factor binding proteins 3 (IGFBP3) and vascular endothelial growth factor (VEGF) were obtained from up-to-date genome-wide association studies (GWAS). Summary-level statistics of MS were obtained from the International Multiple Sclerosis Genetics Consortium, incorporating 14,802 subjects with MS and 26,703 healthy controls of European ancestry. Inverse-variance weighted (IVW) MR was used as the primary method and multiple sensitivity analyses were employed in this study. Results: Genetically predicted circulating levels of FGF23 were associated with risk of MS. The odds ratio (OR) of IVW was 0.63 (95% confidence interval [CI], 0.49-0.82; p < 0.001) per one standard deviation increase in circulating FGF23 levels. Weighted median estimators also suggested FGF23 associated with lower MS risk (OR = 0.67; 95% CI, 0.51-0.87; p = 0.003). While MR-Egger approach provided no evidence of horizontal pleiotropy (intercept = -0.003, p = 0.95). Results of IVW methods provided no evidence for causal roles of GDF1, IGF1, IGFBP3 and VEGF on MS risks, and additional sensitivity analyses confirmed the robustness of these null findings. Conclusion: Our results implied a causal relationship between FGF23 and the risk of MS. Further studies are warranted to confirm FGF23 as a genetically valid target for MS.

The Clinical Value of GDF15 and Its Prospective Mechanism in Sepsis.

Growth differentiation factor 15 (GDF15) is involved in the occurrence and development of many diseases, and there are few studies on its relationship with sepsis. This article aims to explore the clinical value of GDF15 in sepsis and to preliminarily explore its prospective regulatory effect on macrophage inflammation and its functions. We recruited 320 subjects (132 cases in sepsis group, 93 cases in nonsepsis group, and 95 cases in control group), then detected the serum GDF15 levels and laboratory indicators, and further investigated the correlation between GDF15 and laboratory indicators, and also analyzed the clinical value of GDF15 in sepsis diagnosis, severity assessment, and prognosis. In vitro, we used LPS to stimulate THP-1 and RAW264.7 cells to establish the inflammatory model, and detected the expression of GDF15 in the culture medium and cells under the inflammatory state. After that, we added GDF15 recombinant protein (rGDF15) pretreatment to explore its prospective regulatory effect on macrophage inflammation and its functions. The results showed that the serum GDF15 levels were significantly increased in the sepsis group, which was correlated with laboratory indexes of organ damage, coagulation indexes, inflammatory factors, and SOFA score. GDF15 also has a high AUC in the diagnosis of sepsis, which can be further improved by combining with other indicators. The dynamic monitoring of GDF15 levels can play an important role in the judgment and prognosis of sepsis. In the inflammatory state, the expression of intracellular and extracellular GDF15 increased. GDF15 can reduce the levels of cytokines, inhibit M1 polarization induced by LPS, and promote M2 polarization. Moreover, GDF15 also enhances the phagocytosis and bactericidal function of macrophages. Finally, we observed a decreased level of the phosphorylation of JAK1/STAT3 signaling pathway and the nuclear translocation of NF-κB p65 with the pretreatment of rGDF15. In summary, our study found that GDF15 has good clinical application value in sepsis and plays a protective role in the development of sepsis by regulating the functions of macrophages and inhibiting the activation of JAK1/STAT3 pathway and nuclear translocation of NF-κB p65.

ATF4-mediated GDF15 suppresses LPS-induced inflammation and MUC5AC in human nasal epithelial cells through the PI3K/Akt pathway.

AIMS: Growth and differentiation factor 15 (GDF15) is a stress-related factor, which implicated in various diseases. This study aimed to investigate the role of GDF15 in LPS-mediated inflammation and to explore the potential underlying molecular mechanisms in human nasal epithelial cells (HNEpCs). MAIN METHODS: HNEpCs were treated with LPS. GDF15 loss-of-function and gain-of-function experiments were performed. The expression of GDF15 by quantitative real-time PCR (RT-qPCR). The mRNA levels and secretion of inflammatory cytokines and MUC5AC were assessed by RT-qPCR and ELISA kits. LY294002 (PI3K inhibitor) and 740Y-P (PI3K agonist) were utilized to interfere with PI3k/Akt pathway. The relationship between GDF15 and ATF4 was identified by chromatin immunoprecipitation (ChIP) and luciferase reporter assay. KEY FINDINGS: We observed that LPS triggered GDF15 expression. GDF15 ablation reduced the mRNA levels and secretion of inflammatory cytokines. GDF15 silencing led to the reduction of the MUC5AC mRNA level, protein level and secretion in response to LPS. Enhanced expression of GDF15 showed the opposite results. Furthermore, we found that GDF15 deficiency inhibited activation of the PI3K/Akt pathway, LY294002 treatment further enhanced the role of GDF15 suppression in inflammation and MUC5AC expression, while 740Y-P administration partly reversed the biological activities of GDF15 silencing. ATF4 could bind to the promoter of GDF15 and positively regulate GDF15 expression. Depression of ATF4 diminished the secretion of inflammatory cytokines and MUC5AC via regulation of GDF15. SIGNIFICANCE: Our data suggest that GDF15 is regulated by ATF4 and suppresses LPS-induced inflammation and MUC5AC in human nasal epithelial cells through the PI3K/Akt pathway.

Association of GDF15 With Inflammation and Physical Function During Aging and Recovery After Acute Hospitalization: A Longitudinal Study of Older Patients and Age-Matched Controls.

Growth differentiation factor 15 (GDF15) is a stress-induced cytokine. Its plasma levels increase during aging and acute illness. In older Patients and age-matched Controls, we evaluated whether GDF15 levels (i) were associated with recovery after acute illness, and (ii) reflected different trajectories of aging and longitudinal changes in health measures. Fifty-two older Patients (≥65 years) were included upon admission to the emergency department (ED). At 30 days after discharge (time of matching), Patients were matched 1:1 on age and sex with Controls who had not been hospitalized within 2 years of inclusion. Both groups were followed up after 1 year. We assessed plasma levels of GDF15 and inflammatory biomarkers, frailty, nutritional status (mini nutritional assessment short-form), physical and cognitive function, and metabolic biomarkers. In Patients, elevated GDF15 levels at ED admission were associated with poorer resolution of inflammation (soluble urokinase plasminogen activator receptor [suPAR]), slowing of gait speed, and declining nutritional status between admission and 30-day follow-up. At time of matching, Patients were frailer and overall less healthy than age-matched Controls. GDF15 levels were significantly associated with participant group, on average Patients had almost 60% higher GDF15 than age-matched Controls, and this difference was partly mediated by reduced physical function. Increases in GDF15 levels between time of matching and 1-year follow-up were associated with increases in levels of interleukin-6 in Patients, and tumor necrosis factor-α and suPAR in age-matched Controls. In older adults, elevated GDF15 levels were associated with signs of accelerated aging and with poorer recovery after acute illness.

Progressive postnatal motoneuron loss in mice lacking GDF-15.

Growth/differentiation factor-15 (GDF-15) is a widely expressed distant member of the TGF-beta superfamily with prominent neurotrophic effects on midbrain dopaminergic neurons. We show here that GDF-15-deficient mice exhibit progressive postnatal losses of spinal, facial, and trigeminal motoneurons. This deficit reaches a approximately 20% maximum at 6 months and is accompanied by losses of motor axons and significant impairment of rotarod skills. Similarly, sensory neurons in dorsal root ganglia (L4, L5) are reduced by 20%, whereas sympathetic neurons are not affected. GDF-15 is expressed and secreted by Schwann cells, retrogradely transported along adult sciatic nerve axons, and promotes survival of axotomized facial neurons as well as cultured motor, sensory, and sympathetic neurons. Despite striking similarities in the GDF-15 and CNTF knock-out phenotypes, expression levels of CNTF and other neurotrophic factors in the sciatic nerve were unaltered suggesting that GDF-15 is a genuine novel trophic factor for motor and sensory neurons.

NSAID-activated gene-1 as a molecular target for capsaicin-induced apoptosis through a novel molecular mechanism involving GSK3beta, C/EBPbeta and ATF3.

Capsaicin, a natural product of the Capsicum species of red peppers, is known to induce apoptosis and suppress growth. Non-steroidal anti-inflammatory drug-activated gene-1 (NAG-1) is a cytokine associated with pro-apoptotic and antitumorigenic property in colorectal and lung cancer. Our data demonstrate that capsaicin leads to induction of apoptosis and up-regulates NAG-1 gene expression at the transcriptional level. Overexpression of CCAAT/enhancer binding protein beta (C/EBPbeta) caused a significant increase of basal and capsaicin-induced NAG-1 promoter activity. We subsequently identified C/EBPbeta binding sites in the NAG-1 promoter responsible for capsaicin-induced NAG-1 transactivation. Electrophoretic mobility shift assay and chromatin immunoprecipitation assay confirmed binding of C/EBPbeta to the NAG-1 promoter. Capsaicin treatment resulted in an increase of phosphorylated serine/threonine residues on C/EBPbeta, and the immunoprecipitation study showed that capsaicin enhanced binding of C/EBPbeta with glycogen synthase kinase 3beta (GSK3beta) and activating transcription factor 3 (ATF3). The phosphorylation and interaction of C/EBPbeta with GSK3beta and ATF3 are decreased by the inhibition of the GSK3beta and Protein Kinase C pathways. Knockdown of C/EBPbeta, GSK3beta or ATF3 ameliorates NAG-1 expression induced by capsaicin treatment. These data indicate that C/EBPbeta phosphorylation through GSK3beta may mediate capsaicin-induced expression of NAG-1 and apoptosis through cooperation with ATF3 in human colorectal cancer cells.

Growth differentiation factor 15 in anaemia of chronic disease, iron deficiency anaemia and mixed type anaemia.

Recently, the iron and erythropoiesis-controlled growth differentiation factor 15 (GDF15) has been shown to inhibit the expression of hepcidin in beta-thalassaemia patients, thereby increasing iron absorption despite iron overload. To access the diagnostic and pathogenic impact of GDF15 in inflammatory anaemia the association of GDF15 expression with serum iron parameters and hepcidin was studied in patients suffering from iron deficiency anaemia (IDA), anaemia of chronic disease (ACD) and ACD subjects with true iron deficiency (ACD/IDA). GDF15 was significantly increased in both ACD and ACD/IDA, but not in IDA subjects as compared to controls. In contrast, hepcidin levels were significantly lower in IDA and ACD/IDA subjects than in ACD patients. IDA and ACD/IDA, but not ACD, showed an association between GDF15 and soluble transferrin receptor, an indicator of iron requirement for erythropoiesis. However, GDF15 did not correlate to hepcidin in either patient group. While GDF15 levels were linked to the needs for erythropoiesis and iron homeostasis in IDA, the immunity-driven increase of GDF15 may not primarily affect iron homeostasis and hepcidin expression. This indicates that other ACD-related factors may overcome the regulatory effects of GDF15 on hepcidin expression during inflammation.