Magnolol, a compound extracted from Magnolia officinalis, demonstrates potential efficacy in addressing metabolic dysfunction and cardiovascular diseases. Its biological activities encompass anti-inflammatory, antioxidant, anticoagulant, and anti-diabetic effects. Growth/differentiation factor-15 (GDF-15), a member of the transforming growth factor β superfamily, is considered a potential therapeutic target for metabolic disorders. This study investigated the impact of magnolol on GDF-15 production and its underlying mechanism. The research examined the pharmacological effect of magnolol on GDF-15 expression in vitro and in vivo, and determined the involvement of endoplasmic reticulum (ER) stress signaling in this process. Luciferase reporter assays, chromatin immunoprecipitation, and in vitro DNA binding assays were employed to examine the regulation of GDF-15 by activating transcription factor 4 (ATF4), CCAAT enhancer binding protein γ (CEBPG), and CCCTC-binding factor (CTCF). The study also investigated the effect of magnolol and ATF4 on the activity of a putative enhancer located in the intron of the GDF-15 gene, as well as the influence of single nucleotide polymorphisms (SNPs) on magnolol and ATF4-induced transcription activity. Results demonstrated that magnolol triggers GDF-15 production in endothelial cells (ECs), hepatoma cell line G2 (HepG2) and hepatoma cell line 3B (Hep3B) cell lines, and primary mouse hepatocytes. The cooperative binding of ATF4 and CEBPG upstream of the GDF-15 gene or the E1944285 enhancer located in the intron led to full-power transcription of the GDF-15 gene. SNP alleles were found to impact the magnolol and ATF4-induced transcription activity of GDF-15. In high-fat diet ApoE^-/- mice, administration of magnolol induced GDF-15 production and partially suppressed appetite through GDF-15. These findings suggest that magnolol regulates GDF-15 expression through priming of promoter and enhancer activity, indicating its potential as a drug for the treatment of metabolic disorders.
Lignans/pharmacology* ; Growth Differentiation Factor 15/metabolism* ; Animals ; Biphenyl Compounds/pharmacology* ; Endoplasmic Reticulum Stress/drug effects* ; Activating Transcription Factor 4/genetics* ; Mice ; Humans ; Male ; Magnolia/chemistry* ; CCAAT-Enhancer-Binding Proteins/genetics* ; Mice, Inbred C57BL

Treating patients with esophageal squamous cell carcinoma (ESCC) is challenging due to the high chemoresistance. Growth differentiation factor 15 (GDF15) is crucial in the development of various types of tumors and negatively related to the prognosis of ESCC patients according to our previous research. In this study, the link between GDF15 and chemotherapy resistance in ESCC was further explored. The relationship between GDF15 and the chemotherapy response was investigated through in vitro and in vivo studies. ESCC patients with high levels of GDF15 expression showed an inferior chemotherapeutic response. GDF15 improved the tolerance of ESCC cell lines to low-dose cisplatin by regulating AKT phosphorylation via TGFBR2. Through an in vivo study, we further validated that the anti-GDF15 antibody improved the tumor inhibition effect of cisplatin. Metabolomics showed that GDF15 could alter cellular metabolism and enhance the expression of UGT1A. AKT and TGFBR2 inhibition resulted in the reversal of the GDF15-induced expression of UGT1A, indicating that TGFBR2-AKT pathway-dependent metabolic pathways were involved in the resistance of ESCC cells to cisplatin. The present investigation suggests that a high level of GDF15 expression leads to ESCC chemoresistance and that GDF15 can be targeted during chemotherapy, resulting in beneficial therapeutic outcomes.
Humans ; Esophageal Squamous Cell Carcinoma/drug therapy* ; Cisplatin/metabolism* ; Esophageal Neoplasms/metabolism* ; Proto-Oncogene Proteins c-akt/metabolism* ; Carcinoma, Squamous Cell/genetics* ; Growth Differentiation Factor 15/therapeutic use* ; Receptor, Transforming Growth Factor-beta Type II/therapeutic use* ; Cell Line, Tumor ; Cell Proliferation ; Gene Expression Regulation, Neoplastic

Obesity results in an inflammatory microenvironment in adipose tissue, leading to the deterioration of tissue protective mechanisms. Although recent studies suggested the importance of type 2 immunity in an anti-inflammatory microenvironment in adipose tissue, the regulatory effects of T helper 2 (Th2) cytokines on systemic metabolic regulation are not fully understood. Recently, we identified the roles of the Th2 cytokine (interleukin 4 [IL-4] and IL-13)-induced adipokine, growth differentiation factor 15 (GDF15), in adipose tissue in regulating systemic glucose metabolism via signal transducer and activator of transcription 6 (STAT6) activation. Moreover, we showed that mitochondrial oxidative phosphorylation is required to maintain these macrophage-regulating autocrine and paracrine signaling pathways via Th2 cytokine-induced secretion of GDF15. In this review, we discuss how the type 2 immune response and Th2 cytokines regulate metabolism in adipose tissue. Specifically, we review the systemic regulatory roles of Th2 cytokines in metabolic disease and the role of mitochondria in maintenance of type 2 responses in adipose tissue homeostasis.
Adipokines ; Adipose Tissue ; Cytokines ; Glucose ; Growth Differentiation Factor 15 ; Homeostasis ; Metabolic Diseases ; Metabolism ; Mitochondria ; Obesity ; Oxidative Phosphorylation ; Paracrine Communication ; STAT6 Transcription Factor

Growth differentiation factor-15 (GDF-15) is a member of the transforming growth factor beta superfamily. GDF-15 expression is dramatically upregulated during acute brain injury, cancer, cardiovascular disease, and inflammation, suggesting its potential value as a disease biomarker. It has been suggested that GDF-15 has neurotropic effects in the nervous system. Our studies showed that GDF-15 modulated the expression of neuronal Kand Caion channels and increased the release of excitatory transmitter in the medial prefrontal cortex of mice. GDF-15 is also involved in the complex modulation of cancer and cardiovascular disease. Here, we reviewed studies involving the modulation of GDF-15 expression and its mechanisms, the primary pathological and physiological functions of GDF-15 in neurological and cardiovascular systems, and its role in cancer progression. The biological effects and the values of GDF-15 in basic research and clinical applications were also addressed.
Animals ; Brain Injuries ; physiopathology ; Calcium Channels ; metabolism ; Cardiovascular Diseases ; physiopathology ; Disease Progression ; Growth Differentiation Factor 15 ; metabolism ; Humans ; Inflammation ; Mice ; Neoplasms ; physiopathology ; Nervous System ; metabolism ; Potassium Channels ; metabolism ; Prefrontal Cortex ; metabolism ; Transforming Growth Factor beta ; Up-Regulation

OBJECTIVE: To determine the serum level of the growth differentiation factor 15 (GDF15) in multiple myeloma (MM) patients and analyze its level with other clinical parameters, and to investigate its significance in the formation, development and prognosis assessment of MM. METHODS: We used enzyme-linked immunosorbent assay (ELISA) to measure the serum level of GDF15 in an MM group (24 pre-treatment patients) and in 20 healthy controls. All patients' clinical data were collected. RESULTS: The serum GDF15 level was significantly higher in the MM group [(1.37±0.64) ng/mL] than in the normal control group [(0.14±0.06) ng/mL, P<0.01]. The mean serum GDF15 level in the MM patients in ISS stage III was (1.57±0.48) ng/mL, significantly higher than that of ISS stage (I+II) [(0.77±0.34) ng/mL, P<0.05]. There was no significant positive correlation between the serum GDF15 level and serum monoclonal proteins (M protein) level, β2-microglobulin and creatinemia (P<0.05), but significant inverse correlation was found between the GDF15 level with hemoglobin concentration and platelet count respectively (P<0.05). Serum GDF15 level was not associated with patients' age, albumin, lactic dehydrogenase (LDH), C-reactive protein (CRP), calcemia or leukocyte count (P>0.05). After 3 cycles of chemotherapy, patients with a>50% reduction of M protein had a significant reduction of GDF15, while for the patients whose M protein did not decrease obviously, their corresponding serum GDF15 level increased. CONCLUSION The serum GDF15 level may reflect the tumor burden in the MM patients, which increases obviously, is related with ISS, positively correlated with serum M protein level, β2- microglobulin level, serum creatinine and negatively with hemoglobin concentration and platelet count. The change of serum GDF15 level has some relation with the extent of M protein reduction, suggesting it may be used as a marker for therapy response.
Biomarkers, Tumor ; blood ; C-Reactive Protein ; Creatinine ; blood ; Enzyme-Linked Immunosorbent Assay ; Growth Differentiation Factor 15 ; blood ; Humans ; Multiple Myeloma ; blood ; Myeloma Proteins ; metabolism ; Prognosis ; beta 2-Microglobulin ; blood

OBJECTIVETo provide an overview of the current knowledge of growth-differentiation factor 15 (GDF-15) in heart disease.

DATA SOURCESTo identify relevant publications, we searched PubMED database combining the textual terms of heart, cardiac, cardiovascular disease with GDF-15.

STUDY SELECTIONWell-controlled, relatively large-scale, retrospective studies as well as meaningful individual cases were all selected as materials.

RESULTSGDF-15 is a distant member of the transforming growth factor-β cytokine superfamily. In myocardium, GDF-15 is weakly expressed under physiological conditions. However, its expression level is increased in response to pathological stress. Growing evidence indicate that elevated levels of GDF-15 is a promising prognostic biomarker in cardiovascular diseases. Moreover, GDF-15 exhibits the properties of endogenous anti-hypertrophy of cardiomyocytes and protecting the heart suffering from ischemia and reperfusion insult.

CONCLUSIONVe GDF-15 may be a promising biomarker for evaluation and management of patient with cardiovascular diseases, and have potential protective properties on myocardium.

Animals ; Biomarkers ; metabolism ; Cardiovascular Diseases ; metabolism ; Growth Differentiation Factor 15 ; metabolism ; Humans ; Stress, Physiological ; physiology

BACKGROUNDThe aim of this research was to determine the efficacy of combination therapy using an alginate dressing and mouse epidermal growth factor (mEGF) on proliferation and differentiation of epidermal stem cells (ESCs) in patients with refractory wounds.

METHODSEighteen patients (12 males and 6 females, aged from 18 to 61 years (mean 36.4 years)) with various skin wounds, were treated by dressing changing for one month. The wounds were located in the foot (11), calf (3), thigh (2) and forearm (2). The patients were randomly divided into 3 groups: alginate dressing and mEGF (group A; n = 6), mEGF (group B; n = 6) and control (group C; n = 6). Wound closure indexes were measured at 7, 14, 21 and 28 days. Samples were harvested for pathologic examination, at 7 and 14 days following treatment. Cytokeratin 10 (CK10) and cytokeratin 15 (CK15) positive cells were evaluated using the super-sensitivity (SP) immunohistochemical staining technique.

RESULTSWound healing was promoted in groups A and B. In group A, the wound closure index was increased significantly (P < 0.05), and in one case the maximum cure area reached 102 cm(2). Pathological examination identified a thicker epidermis, active angiogenesis and enhanced granulation in group A compared with groups B and C. Using the SP immunohistochemical staining technique, we showed that ESCs in group A were bigger in size and larger in number than in groups B and C. Overall, there was a significant difference in ESCs proliferation and differentiation between group A and group B (or C).

CONCLUSIONSCombination therapy using an alginate dressing and mEGF shows increased proliferation and differentiation of ESCs in patients with refractory wounds compared with those treated with mEGF alone.

Adolescent ; Adult ; Alginates ; therapeutic use ; Animals ; Bandages ; Cell Differentiation ; drug effects ; Cell Proliferation ; drug effects ; Epidermal Growth Factor ; therapeutic use ; Epithelial Cells ; cytology ; Female ; Glucuronic Acid ; therapeutic use ; Hexuronic Acids ; therapeutic use ; Humans ; Immunohistochemistry ; Keratin-15 ; metabolism ; Male ; Mice ; Middle Aged ; Stem Cells ; cytology ; drug effects ; Wound Healing ; drug effects ; Young Adult

Ineffective erythropoiesis is recognized as the principal reason of non-transfusional iron overload. In the process of expanded erythropoiesis, the apoptosis of erythroblasts induces the up-regulation of GDF15. GDF15 suppresses hepcidin production by the hepatocytes. Subsequently, low hepcidin levels increase iron absorption from the intestine resulting in iron overload. Physiological dose of GDF15 can promote the growth and differentiation of erythroid progenitors, but the high dose of GDF15 can suppress the secretion of hepcidin. The regulation of GDF15 may also be related to iron levels, epigenetic regulation and hypoxia. In this article the GDF15 and its expression and distribution, roles of GDF15 in erythropoiesis and iron overload, as well as the regulation factors of GDF15 are reviewed.
Erythropoiesis ; Growth Differentiation Factor 15 ; metabolism ; Humans ; Iron Overload

BACKGROUNDThe present study was designed to examine and analyze the global gene expression changes during the tumorigenesis of a human immortalized oral epithelial cell line, and search for the possible genes that may play a role in the carcinogenesis of oral cancer associated with benzo (a) pyrene.

METHODSThe human immortalized oral epithelial cells, which have been established through transfection of E6/E7 genes of human papillomavirus type 16 and proved to be non-tumorigenic in nude mice, were treated with benzo (a) pyrene. Tumorigenicity of the treated cells were examined through nude mice subcutaneous injection. The global gene expression profiles of immortalized cells and the tumorigenic cells were acquired through hybridization of a microarray of Affymetrix U133 plus 2.0. The data were analyzed using Spring 7.0 software and treated statistically using one-way analysis of variance (ANOVA). The differentially expressed genes were classified using a Venn diagram and annotated with gene ontology. Several highlighted genes were validated in cells using a real-time polymerase chain reaction.

RESULTSThere were 883 differentially expressed genes during the tumorigenesis and most of them changed expression in the early stage of tumorigenesis. These genes mainly involved in macromolecule metabolism and signal transduction, possessed the molecular function of transition metal ion binding, nucleotide binding and kinase activity; their protein products were mainly integral to membranes or localized in the nucleus and cytoskeleton. The expression patterns of IGFBP3, S100A8, MAP2K, KRT6B, GDF15, MET were validated in cells using a real-time polymerase chain reaction; the expression of IGFBP3 was further validated in clinical oral cancer specimens.

CONCLUSIONSThis study provides the global transcription profiling associated with the tumorigenesis of oral epithelial cells exposed to benzo (a) pyrene; IGFBP3 may play a potential role in the initiation of oral cancer related to benzo (a) pyrene exposure.

Benzo(a)pyrene ; toxicity ; Cell Transformation, Neoplastic ; Cells, Cultured ; Connexin 43 ; genetics ; Gene Expression Profiling ; Growth Differentiation Factor 15 ; genetics ; Humans ; Insulin-Like Growth Factor Binding Protein 3 ; Insulin-Like Growth Factor Binding Proteins ; genetics ; Mouth Neoplasms ; chemically induced ; metabolism ; Oligonucleotide Array Sequence Analysis ; Reverse Transcriptase Polymerase Chain Reaction

OBJECTIVETo evaluate the levels of bone morphogenetic protein-15 (BMP-15) in human follicular fluid (FF) and its association with response to ovarian stimulation.

METHODSWestern blotting was performed to determine the levels of BMP-15 in FF obtained from follicle aspirates in 70 patients undergoing IVF treatment. According to the response to ovarian stimulation the patients were divided into poor responder group and normal responder group.

RESULTBMP-15 levels in FF of poor responders were significantly higher than those in normal responders (1.01 +/- 0.34 vs 0.77 +/- 0.24, P<0.01).

CONCLUSIONIncreased levels of BMP-15 in FF may be associated with poor response to ovarian stimulation.

Adult ; Blotting, Western ; Bone Morphogenetic Protein 15 ; Female ; Follicle Stimulating Hormone ; administration & dosage ; Follicular Fluid ; drug effects ; metabolism ; Gonadotropin-Releasing Hormone ; administration & dosage ; analogs & derivatives ; Growth Differentiation Factor 9 ; Humans ; Infertility, Female ; metabolism ; Intercellular Signaling Peptides and Proteins ; biosynthesis ; Ovary ; drug effects ; metabolism ; Ovulation Induction