• GDF15
• GFRAL
• biomarker
• inflammation
• neurodegeneration
• neurotrauma
• neurotrophic

• Growth Differentiation Factor 15/metabolism
• Humans
• Neurodegenerative Diseases/metabolism
• Neurodegenerative Diseases/drug therapy
• Biomarkers
• Animals
• Neuroprotective Agents/therapeutic use
• Neuroprotective Agents/pharmacology
• Neuroprotection

• Brown adipose tissue
• Central nervous system diseases
• FGF21
• GDF15
• Irisin

• Animals
• Humans
• Adipose Tissue, Brown/metabolism
• Signal Transduction
• Central Nervous System Diseases/metabolism
• Mammals

• Cardiac biomarkers
• Cardiovascular disease
• Cognitive function
• Dementia
• Mendelian randomization
• Older adults

• Humans
• Mendelian Randomization Analysis
• Genome-Wide Association Study
• Prospective Studies
• Troponin T/genetics
• Troponin I/genetics
• Dementia/genetics
• Biomarkers
• Cognition

• GDF-15
• Parkinson’s disease
• multiple system atrophy
• parkinsonian syndrome
• progressive supranuclear palsy

• JP21K15699 Japan Society for the Promotion of Science

• DNA damage
• Mitochondria nucleus communication
• Mitochondrial damage
• Neurodegeneration
• Stress signalling

• Cell Communication
• Cell Nucleus/genetics
• DNA Damage
• Humans
• Mitochondria/metabolism
• Neurodegenerative Diseases/metabolism

Parkinson’s disease (PD) is the second most common neurodegenerative disorder worldwide. Mitochondrial dysfunction is suspected as one of the pathogenic mechanisms of PD. Growth/differentiation Factor-15 (GDF15) has been reported to affect mitochondrial function in PD. However, the relationship between mitochondrial function and GDF15 induction has not been explained well. Hence, we aimed to reveal the effect of GDF15 induction on SH-SY5Y cells with rotenone toxicity, a cell model of PD.

SH-SY5Y cells were exposed to 1 μM rotenone as a PD model. Cells were transfected with a GDF15-overexpression plasmid and empty vector. We then analyzed the expression level of GDF15, BCL-2/BAX, P53, PGC1-α, α-syn, and TH in GDF15-overexpressing cells by western blotting, enzyme-linked immunosorbent assay, and quantitative real-time polymerase chain reaction. The cytotoxicity of rotenone was measured by CCK-8 assays. Cell apoptosis was detected by flow cytometric and TUNEL assays. The effect of GDF15 on oxidative stress and mitochondrial function was revealed using DCFH-DA, mito-SOX, and JC-10 assays and a Seahorse XF Cell Mito Stress Test.

GDF15 protected rotenone-treated SH-SY5Y cells from toxicity by preserving mitochondrial function and decreasing apoptosis, during which GDF15 might function by influencing PGC1α through the regulation of p53. In addition, GDF15 overexpression could improve Akt and mTOR phosphorylation, leading to PI3K/Akt/mTOR pathway activation. However, these protective effects were eliminated when cells were treated with the PI3K/Akt specific inhibitor LY294002.

Our findings suggest that GDF15 can protect mitochondrial function and inhibit apoptosis in SH-SY5Y cells after exposure to rotenone by upregulating PGC1α via p53. These properties might comprise its anti-apoptotic effects, mediated by the PI3K/Akt/mTOR signaling pathway.

• Age-related diseases
• Dormancy program
• GDF15
• Inflammaging
• Metabolism
• Stress

• Aging/metabolism
• Growth Differentiation Factor 15/metabolism
• Humans
• Respiratory Distress Syndrome

Identifying genes with the largest expression changes (gene selection) to characterize a given condition is a popular first step to drive exploration into molecular mechanisms and is, therefore, paramount for therapeutic development. Reproducibility in the sciences makes it necessary to emphasize objectivity and systematic repeatability in biological and informatics analyses, including gene selection. With these two characteristics in mind, in previous works our research team has proposed using multiple criteria optimization (MCO) in gene selection to analyze microarray datasets. The result of this effort is the MCO algorithm, which selects genes with the largest expression changes without user manipulation of neither informatics nor statistical parameters. Furthermore, the user is not required to choose either a preference structure among multiple measures or a predetermined quantity of genes to be deemed significant a priori. This implies that using the same datasets and performance measures (PMs), the method will converge to the same set of selected differentially expressed genes (repeatability) despite who carries out the analysis (objectivity). The present work describes the development of an open-source tool in RStudio to enable both: (1) individual analysis of single datasets with two or three PMs and (2) meta-analysis with up to five microarray datasets, using one PM from each dataset. The capabilities afforded by the code include license-free portability and the possibility to carry out analyses via modest computer hardware, such as personal laptops. The code provides affordable, repeatable, and objective detection of differentially expressed genes from microarrays. It can be used to analyze other experiments with similar experimental comparative layouts, such as microRNA arrays and protein arrays, among others. As a demonstration of the capabilities of the code, the analysis of four publicly-available microarray datasets related to Parkinson´s Disease (PD) is presented here, treating each dataset individually or as a four-way meta-analysis. These MCO-supported analyses made it possible to identify MMP9 and TUBB2A as potential PD genetic biomarkers based on their persistent appearance across each of the case studies. A literature search confirmed the importance of these genes in PD and indeed as PD biomarkers, which evidences the code´s potential.

• GDF15
• diagnostic utility
• meta-analysis
• neurodegenerative diseases

• the Israel Science Foundation

Brain disorders, such as Alzheimer's and Parkinson's disease and cerebral stroke, are an important contributor to mortality and disability worldwide, where their pathogenesis is currently a topic of intense research. The mechanisms underlying the development of brain disorders are complex and vary widely, including aberrant protein aggregation, ischemic cell necrosis and neuronal dysfunction. Previous studies have found that the expression and function of growth differentiation factor-15 (GDF15) is closely associated with the incidence of brain disorders. GDF15 is a member of the TGFβ superfamily, which is a dimer-structured stress-response protein. The expression of GDF15 is regulated by a number of proteins upstream, including p53, early growth response-1, non-coding RNAs and hormones. In particular, GDF15 has been reported to serve an important role in regulating angiogenesis, apoptosis, lipid metabolism and inflammation. For example, GDF15 can promote angiogenesis by promoting the proliferation of human umbilical vein endothelial cells, apoptosis of prostate cancer cells and fat metabolism in fasted mice, and GDF15 can decrease the inflammatory response of lipopolysaccharide-treated mice. The present article reviews the structure and biosynthesis of GDF15, in addition to the possible roles of GDF15 in Alzheimer's disease, cerebral stroke and Parkinson's disease. The purpose of the present review is to summarize the mechanism underlying the role of GDF15 in various brain disorders, which hopes to provide evidence and guide the prevention and treatment of these debilitating conditions.

• Alzheimer's disease
• Parkinson's disease
• brain disorders
• cerebral stroke
• growth differentiation factor-15

• astrocyte phenotype
• astrocyte reactivity
• astrocyte state
• astroglia
• protein markers
• reactive astrogliosis

• Aging/metabolism
• Animals
• Astrocytes/metabolism
• Biomarkers/metabolism
• Brain/metabolism
• Cell Communication
• Glial Fibrillary Acidic Protein/metabolism
• Humans

Growth differentiation factor 15 (GDF15) increases in serum during pregnancy to levels not seen in any other physiological state and is suggested to be involved in pregnancy-induced nausea, weight regulation and glucose metabolism. The main action of GDF15 is regulated through a receptor of the brainstem, i.e., through exposure of GDF15 in both blood and cerebrospinal fluid (CSF). The aim of the current study was to measure GDF15 in both CSF and serum during pregnancy, and to compare it longitudinally to non-pregnant levels.

Women were sampled at elective caesarean section (n = 45, BMI = 28.1±5.0) and were followed up 5 years after pregnancy (n = 25). GDF15, insulin and leptin were measured in CSF and serum. Additional measurements included plasma glucose, and serum adiponectin and Hs-CRP.

GDF15 levels were higher during pregnancy compared with follow-up in both CSF (385±128 vs. 115±32 ng/l, P<0.001) and serum (73789±29198 vs. 404±102 ng/l, P<0.001). CSF levels correlated with serum levels during pregnancy (P<0.001), but not in the non-pregnant state (P = 0.98). Both CSF and serum GDF15 were highest in women carrying a female fetus (P<0.001). Serum GDF15 correlated with the homeostatic model assessment for beta-cell function and placental weight, and CSF GDF15 correlated inversely with CSF insulin levels.

This, the first study to measure CSF GDF15 during pregnancy, demonstrated increased GDF15 levels in both serum and CSF during pregnancy. The results suggest that effects of GDF15 during pregnancy can be mediated by increases in both CSF and serum levels.

• Adiponectin/blood
• Adult
• Blood Glucose/analysis
• C-Reactive Protein/analysis
• Cesarean Section
• Female
• Follow-Up Studies
• Growth Differentiation Factor 15/blood
• Growth Differentiation Factor 15/cerebrospinal fluid
• Humans
• Insulin/blood
• Leptin/blood
• Placenta/physiology
• Pregnancy

• Emil och Wera Cornells Stiftelse
• Vetenskapsrådet
• Diabetesfonden
• the Swedish state under the agreement between the Swedish government and the country councils, the ALF-agreement
• Vetenskapsrådet (Swedish research council)
• Alzheimer's Drug Discovery Foundation
• Hjärnfonden
• H2020 European Research Council
• Åhlén-stiftelsen
• European Union Joint Program for Neurodegenerative Disorders

Elevated levels of tenascin-C are linked to increased risk and severity of major depressive disorder (MDD), while testosterone shows a protective effect. The present study explored associations between serum levels of tenascin-C and testosterone in Chinese men with MDD.

Testosterone and tenascin-C levels were measured in sera of 412 men with MDD and 237 age- and sex-matched controls. Serum levels of thyroid hormone, lipids, and high-sensitivity C-reactive protein (hs-CRP) were also quantified. Potential associations were examined using covariance, subgroup analysis, and multivariate linear regression analyses.

Significantly higher concentrations of tenascin-C were detected in sera of subjects with MDD than in controls. Among subjects with MDD, testosterone concentrations inversely correlated with tenascin-C levels. This relationship was observed when patients were stratified by age at onset; duration or severity of depression; or concentration of thyroid hormones, low- or high-density lipoprotein, or hs-CRP. The negative association remained even when the statistical model was adjusted for age, smoking status, alcohol use, and body mass index. Linear regression with bootstrap resampling confirmed that high tenascin-C levels inversely correlated with testosterone levels.

In men with MDD, high tenascin-C concentrations correlate with testosterone deficiency. The combination of elevated tenascin-C and testosterone deficiency may be associated with MDD progression.

• major depressive disorder
• tenascin-C
• testosterone

Growth Differentiation Factor 15 (GDF15) was previously identified as a molecular marker of retinal ganglion cell stress in rodent models of glaucoma and was elevated in the aqueous humor (AH) of patients with primary open-angle glaucoma as a possible risk factor for glaucoma progression. The purpose of this study was to determine whether changes in the AH GDF15 levels were associated with intraocular pressure (IOP) changes in eyes undergoing glaucoma surgery.

Here, we performed a prospective, longitudinal pilot study in nine patients to determine whether changes in AH GDF15 levels from surgery to post-surgery follow-up were associated with IOP fluctuation. An initial AH sample was taken from the peripheral corneal paracentesis during planned glaucoma surgery, and a second sample was taken during an outpatient follow-up visit, approximately six months later.

There was a statistically significant correlation between GDF15 fold change and IOP standard deviation (r = 0.87, P = 0.003), IOP range (r = 0.87, P = 0.003), and maximum IOP (r = 0.86, P = 0.003). There was no correlation between the GDF15 fold change and baseline IOP (r = 0.50, P = 0.17), final IOP (r = 0.038, P = 0.92), or mean IOP (r = 0.40, P = 0.28).

Our findings in this pilot study suggest that longitudinal changes in AH GDF15 may be associated with IOP fluctuation during the postoperative period. Further studies are necessary to corroborate these findings in a larger patient population and to explore the possibility that AH GDF15 may be used not only to improve treatment algorithms but also as a surrogate endpoint in clinical trials.

• Glaucoma
• Molecular Markers
• Neurodegeneration
• GDF15

• AD
• Aging
• FGF21
• GDF15
• Humanin
• T2D

• Aged, 80 and over
• Alzheimer Disease
• Diabetes Mellitus, Type 2
• Fibroblast Growth Factors
• Growth Differentiation Factor 15
• Healthy Aging
• Humans
• Intracellular Signaling Peptides and Proteins

• Roberto and Cornelia Pallotti's Legacy for Cancer Research
• DPM-AGEING
• Ricerca Finalizzata giovani ricercatori
• JPI-HDHL-Metadis
• Italian Ministry of Health (Ricerca Corrente)

• Cancer
• Energy homeostasis
• GDF15
• GFRAL
• TGFβ

Multiple system atrophy (MSA) is a serious progressive neurodegenerative disease. Early diagnosis of MSA is very difficult, and diagnostic biomarkers are limited. Growth differentiation factor 15 (GDF15) is involved in the differentiation and progression of the central nervous system, and is widely distributed in peripheral blood, which may be a novel biomarker for MSA.

To determine serum GDF15 levels, related factors and their potential diagnostic value in MSA patients, compared with Parkinson’s disease (PD) patients and healthy controls.

A case-control study was conducted, including 49 MSA patients, 50 PD patients and 50 healthy controls. Serum GDF15 levels were measured by human enzyme-linked immunosorbent assay, and the differences between the MSA, PD and control groups were analyzed. Further investigations were performed in different MSA subgroups according to age of onset, sex, clinical subtypes, diagnostic criteria, and disease duration. Receiver-operating characteristic curve analysis was used to evaluate the diagnostic value of GDF15, especially for the differential diagnosis between MSA and PD.

Serum GDF15 levels were significantly higher in MSA patients than in PD patients and healthy controls (P = 0.000). Males and those with a disease duration of more than three years showed higher serum GDF15 levels (P = 0.043 and 0.000; respectively). Serum GDF15 levels may be a potential diagnostic biomarker for MSA patients compared with healthy controls and PD patients (cutoff: 470.42 pg/mL, sensitivity: 85.7%, specificity: 88.0%; cutoff: 1075.91 pg/mL, sensitivity: 51.0%, specificity: 96.0%; respectively).

Serum GDF15 levels are significantly higher in MSA patients and provide suggestions on the etiology of MSA.

• Multiple system atrophy
• Parkinson’s disease
• Serum growth differentiation factor 15
• Biomarker
• Receiver-operating characteristic curve
• Neurodegenerative disease

• Parkinson's disease
• astrocyte
• neurodegeneration
• neuroprotection
• trophic factors

• HT22 cells
• PI3K/Akt signaling pathway
• Parkinson's disease
• growth differentiation factor 15
• mitochondrial function

• Age-related diseases
• Biomarker panel
• Frailty
• Hallmark of aging pathways

• Biomarker
• Clinical features
• Controversy
• Dementia with Lewy bodies
• Diagnostic criteria
• Diagnostic tests
• Management
• Neuropathology
• Parkinson’s disease-dementia

• Humans
• Lewy Body Disease/complications
• Lewy Body Disease/pathology
• Lewy Body Disease/physiopathology
• Parkinson Disease/complications
• Parkinson Disease/pathology
• Parkinson Disease/physiopathology

Accumulating evidence suggests that GDF15 is a biomarker for ageing and morbidity of many somatic disorders such as cancer and inflammatory disorders. Recently, elevated serum GDF15 level was proposed as a marker for mood disorder. However, psychosis severity was not investigated in relation to plasma GDF15 levels. In the present study we measured GDF15 levels in plasma of 120 psychosis patients compared to 120 age and gender matched healthy controls. Within the patient cohort GDF15 levels were evaluated for association with age, gender, lifestyle factors, C-reactive protein levels, psychosis severity and metabolic disorder. Psychosis patients had elevated GDF15 levels compared to controls (median_Psychosis = 744 ng/mL, median_controls = 516 ng/mL, p < 0.001). Within the psychosis cohort, GDF15 levels, when corrected for age, metabolic health and lifestyle factors, were negatively correlated with psychosis severity (β = −0.218, p = 0.012). While GDF15 levels were elevated in patients versus healthy controls, the negative correlation between psychosis severity and GDF15 suggests a loss of anti-inflammatory GDF15 mediated functionality in severe psychosis. Study replication in larger cohorts will be necessary to assess the potential of GDF15 as a prognostic biomarker in psychosis.

• Biomarker
• Growth differentiation factor 15
• Parkinson disease