ABSTRACT
We performed a matched-pair analysis of the content of GDF11 and GDF15 proteins in the plasma of patients (56 middle-aged men) with obstructive sleep apnea syndrome (OSAS) and healthy volunteers (27 men with no complaints of sleep disorders). The groups were comparable in terms of age and presence of chronic diseases. No statistically significant differences in GDF11 content in the studied groups were revealed, while the content of GDF15 in the OSAS group was 1.3 times higher. These results require further research from the viewpoint of geriatric somnology and molecular biology.
Subject(s)
Bone Morphogenetic Proteins , Growth Differentiation Factor 15 , Growth Differentiation Factors , Sleep Apnea, Obstructive , Humans , Male , Growth Differentiation Factors/blood , Pilot Projects , Middle Aged , Growth Differentiation Factor 15/blood , Bone Morphogenetic Proteins/blood , Sleep Apnea, Obstructive/blood , Case-Control Studies , Bone Morphogenetic Protein 15/blood , Bone Morphogenetic Protein 15/genetics , Adult , Sleep Apnea Syndromes/blood , AgedABSTRACT
In recent years, a common-used antidiabetic drug, liraglutide, was identified with extra effects on lipid metabolism. Its effects against excessive lipid deposition in bone marrow were gained much attention but not well established. Our aim in the present study is to explore the interaction of miRNAs-mRNAs altered by liraglutide administration during bone marrow adipogenesis in diabetes. To establish the diabetic animal model, rats were treated with high fat diet (HFD) and STZ injection. We then identified the lowering effect of liraglutide on lipids metabolism in the diabetes. During this process, high-throughput sequencing and bioinformatics analyses on miRNAs extracted from bone marrow mesenchymal stem cells (BMSCs) were conducted after liraglutide administration. We then identified five differentially expressed miRNAs (miRNA-150-5p, miRNA-129-5p, miRNA-201-3p, miRNA-201-5p, and miRNA-214-5p). The expressions of the DE miRNAs were verified as temporal specific expression patterns in Day 3 and in Day 7. Among them, miRNA-150-5p expression was more stable and consistent with the sequencing data. Of interest, miR-150-5p overexpression facilitated adipogenesis of BMSCs. But this promotion was alleviated by liraglutide. The predicted target gene of miR-150-5p, GDF11, was validated to be involved in liraglutide alleviated BMSCs' lipid accumulation in diabetes. In vitro, liraglutide increased the GDF11 expression, rescued its down-expression by siGDF11 and inhibit the adipogenesis of BMSCs cultured in high glucose medium. In vivo, liraglutide reversed the HFD-STZ induced excessive lipid droplets by up-regulation of GDF11 expression, which was discounted by agomiR-150-5p injection. Above all, liraglutide might alleviate bone marrow fat accumulation via inactivating miR-150-5p/GDF11 axis in diabetes.
Subject(s)
Adipogenesis , Diabetes Mellitus, Experimental , Liraglutide , Mesenchymal Stem Cells , MicroRNAs , Rats, Sprague-Dawley , Animals , MicroRNAs/genetics , MicroRNAs/metabolism , Liraglutide/pharmacology , Liraglutide/therapeutic use , Male , Diabetes Mellitus, Experimental/drug therapy , Diabetes Mellitus, Experimental/metabolism , Adipogenesis/drug effects , Adipogenesis/genetics , Rats , Mesenchymal Stem Cells/drug effects , Mesenchymal Stem Cells/metabolism , Growth Differentiation Factors/genetics , Growth Differentiation Factors/metabolism , Bone Morphogenetic Proteins/metabolism , Bone Morphogenetic Proteins/genetics , Bone Marrow/drug effects , Bone Marrow/metabolism , Diet, High-Fat/adverse effects , Hypoglycemic Agents/pharmacology , Hypoglycemic Agents/therapeutic use , Gene Expression Regulation/drug effects , Lipid Metabolism/drug effects , Lipid Metabolism/genetics , Bone Marrow Cells/drug effects , Bone Marrow Cells/metabolismABSTRACT
ABSTRACT: Sepsis is a lethal clinical syndrome, and acute lung injury (ALI) is the earliest and most serious complication. We aimed to explore the role of growth differentiation factor 11 (GDF11) in sepsis-induced dysfunction of lung microvascular endothelial barrier in vivo and in vitro to elucidate its potential mechanism related to sirtuin 1 (SIRT1)/NADPH oxidase 4 (NOX4) signaling. Cecal ligation and puncture (CLP)-induced sepsis mice and lipopolysaccharide (LPS)-induced pulmonary microvascular endothelial cells (PMECs) were used in this study. Histopathological changes in lung tissues were tested by hematoxylin-eosin staining. Lung wet-to-dry weight ratio and inflammatory factors contents in bronchoalveolar lavage fluid were assessed. Evens blue index, trans-epithelial electrical resistance, and expression of zona occludens 1 (ZO-1), occludin-1, and claudin-1 were used to evaluate alveolar barrier integrity. Reactive oxygen species, lipid peroxidation, and ferroptosis markers were analyzed. Iron deposition in the lung tissues was assessed using Prussian blue staining. Intracellular Fe 2+ level was detected using FerroOrange staining. Additionally, expression of GDF11, SIRT1, and NOX4 was estimated with western blot. Then, EX527, a SIRT1 inhibitor, was employed to treat GDF11-overexpressed PMECs with LPS stimulation to clarify the regulatory mechanism. Results showed that GDF11 overexpression attenuated sepsis-induced pathological changes and inflammation and maintained alveolar barrier integrity. Moreover, GDF11 overexpression inhibited ferroptosis, upregulated SIRT1 expression and downregulated NOX4 expression. Additionally, EX527 treatment relieved the impacts of GDF11 overexpression on ferroptosis and destruction of integrity of human pulmonary microvascular endothelial cells exposed to LPS. Taken together, GDF11 overexpression could alleviate sepsis-induced lung microvascular endothelial barrier damage by activating SIRT1/NOX4 signaling to inhibit ferroptosis. Our findings potentially provide new molecular target for clinical therapy of ALI.
Subject(s)
Ferroptosis , Growth Differentiation Factors , Lung , NADPH Oxidase 4 , Sepsis , Signal Transduction , Sirtuin 1 , Animals , Sirtuin 1/metabolism , NADPH Oxidase 4/metabolism , Sepsis/metabolism , Sepsis/complications , Mice , Male , Growth Differentiation Factors/metabolism , Lung/pathology , Lung/metabolism , Mice, Inbred C57BL , Acute Lung Injury/metabolism , Endothelial Cells/metabolism , Bone Morphogenetic ProteinsABSTRACT
BACKGROUND: The cognitive decline associated with type 2 diabetes (T2D) is often attributed to compromised hippocampal neurogenesis and exacerbated neural inflammation. This study investigates the therapeutic potential of growth differentiation factor 11 (GDF11) in reversing these neurodegenerative processes in diabetic mice. RESULT: We utilized a murine model of T2D and examined the effects of GDF11 on learning, memory, neurogenesis, and neuroinflammatory markers. Our results indicate that diabetic mice exhibit significant deficits in cognitive function, mirrored by reduced hippocampal neurogenesis and increased neuroinflammation. Chronic administration of GDF11 was observed to significantly enhance cognitive abilities, as evidenced by improved performance in learning and memory tasks. Concurrently, GDF11 treatment restored neural activity and promoted the regeneration of new neurons within the hippocampus. Inflammatory profiling revealed a reduction in neuroinflammatory markers, which was further supported by reduced microglia numbers. To delineate the role of neuroinflammation, we pharmacologically depleted microglia, leading to a restoration of neurogenesis and cognitive functions in diabetic mice. CONCLUSION: These findings endorse the hypothesis that GDF11 exerts its beneficial effects by modulating neuroinflammatory pathways. Consequently, GDF11 represents a promising intervention to ameliorate diabetes-induced cognitive impairments and neural degeneration through its anti-inflammatory properties.
Subject(s)
Bone Morphogenetic Proteins , Cognition , Diabetes Mellitus, Experimental , Diabetes Mellitus, Type 2 , Growth Differentiation Factors , Hippocampus , Neurogenesis , Neuroinflammatory Diseases , Animals , Neurogenesis/drug effects , Neurogenesis/physiology , Growth Differentiation Factors/metabolism , Growth Differentiation Factors/pharmacology , Hippocampus/metabolism , Mice , Diabetes Mellitus, Experimental/metabolism , Diabetes Mellitus, Experimental/complications , Cognition/drug effects , Cognition/physiology , Male , Neuroinflammatory Diseases/metabolism , Bone Morphogenetic Proteins/metabolism , Diabetes Mellitus, Type 2/metabolism , Diabetes Mellitus, Type 2/complications , Cognitive Dysfunction/metabolism , Cognitive Dysfunction/drug therapy , Cognitive Dysfunction/etiology , Mice, Inbred C57BL , Microglia/metabolism , Microglia/drug effects , Inflammation/metabolism , Memory/drug effects , Memory/physiology , Neurons/metabolismABSTRACT
BACKGROUND: Diabetic cardiomyopathy (DCM) is a crucial complication of long-term chronic diabetes that can lead to myocardial hypertrophy, myocardial fibrosis, and heart failure. There is increasing evidence that DCM is associated with pyroptosis, a form of inflammation-related programmed cell death. Growth differentiation factor 11 (GDF11) is a member of the transforming growth factor ß superfamily, which regulates oxidative stress, inflammation, and cell survival to mitigate myocardial hypertrophy, myocardial infarction, and vascular injury. However, the role of GDF11 in regulating pyroptosis in DCM remains to be elucidated. This research aims to investigate the role of GDF11 in regulating pyroptosis in DCM and the related mechanism. METHODS AND RESULTS: Mice were injected with streptozotocin (STZ) to induce a diabetes model. H9c2 cardiomyocytes were cultured in high glucose (50 mM) to establish an in vitro model of diabetes. C57BL/6J mice were preinjected with adeno-associated virus 9 (AAV9) intravenously via the tail vein to specifically overexpress myocardial GDF11. GDF11 attenuated pyroptosis in H9c2 cardiomyocytes after high-glucose treatment. In diabetic mice, GDF11 alleviated cardiomyocyte pyroptosis, reduced myocardial fibrosis, and improved cardiac function. Mechanistically, GDF11 inhibited pyroptosis by preventing inflammasome activation. GDF11 achieved this by specifically binding to apoptosis-associated speck-like protein containing a CARD (ASC) and preventing the assembly and activation of the inflammasome. Additionally, the expression of GDF11 during pyroptosis was regulated by peroxisome proliferator-activated receptor α (PPARα). CONCLUSION: These findings demonstrate that GDF11 can treat diabetic cardiomyopathy by alleviating pyroptosis and reveal the role of the PPARα-GDF11-ASC pathway in DCM, providing ideas for new strategies for cardioprotection.
Subject(s)
Diabetes Mellitus, Experimental , Diabetic Cardiomyopathies , Fibrosis , Growth Differentiation Factors , Inflammasomes , Mice, Inbred C57BL , Myocytes, Cardiac , Pyroptosis , Signal Transduction , Animals , Pyroptosis/drug effects , Diabetic Cardiomyopathies/metabolism , Diabetic Cardiomyopathies/pathology , Diabetic Cardiomyopathies/prevention & control , Diabetic Cardiomyopathies/etiology , Diabetic Cardiomyopathies/physiopathology , Myocytes, Cardiac/metabolism , Myocytes, Cardiac/pathology , Myocytes, Cardiac/drug effects , Diabetes Mellitus, Experimental/metabolism , Cell Line , Inflammasomes/metabolism , Male , Growth Differentiation Factors/metabolism , Rats , Blood Glucose/metabolism , Mice , Glucose/metabolism , Glucose/toxicity , Bone Morphogenetic Proteins , PPAR alphaABSTRACT
Growth differentiation factor 11 (GDF11), also known as bone morphogenetic protein 11 (BMP11), has been identified as a key player in various biological processes, including embryonic development, aging, metabolic disorders and cancers. GDF11 has also emerged as a critical component in liver development, injury and fibrosis. However, the effects of GDF11 on liver physiology and pathology have been a subject of debate among researchers due to conflicting reported outcomes. While some studies suggest that GDF11 has anti-aging properties, others have documented its senescence-inducing effects. Similarly, while GDF11 has been implicated in exacerbating liver injury, it has also been shown to have the potential to reduce liver fibrosis. In this narrative review, we present a comprehensive report of recent evidence elucidating the diverse roles of GDF11 in liver development, hepatic injury, regeneration and associated diseases such as non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), liver fibrosis and hepatocellular carcinoma. We also explore the therapeutic potential of GDF11 in managing various liver pathologies.
Subject(s)
Liver Neoplasms , Non-alcoholic Fatty Liver Disease , Humans , Non-alcoholic Fatty Liver Disease/drug therapy , Non-alcoholic Fatty Liver Disease/genetics , Non-alcoholic Fatty Liver Disease/metabolism , Fibrosis , Liver Cirrhosis/pathology , Growth Differentiation Factors/genetics , Growth Differentiation Factors/metabolism , Bone Morphogenetic Proteins/genetics , Bone Morphogenetic Proteins/metabolism , Liver Neoplasms/pathologyABSTRACT
Objective: To investigate the correlation between serum growth differentiation factor 11 (GDF11) level and coronary artery lesions in patients with ST-segment elevation myocardial infarction (STEMI), and the predictive efficacy of nomogram risk prediction model based on GDF11 combined with traditional risk factors on the occurrence of STEMI. Methods: This study was a retrospective cross-sectional study. Patients hospitalized in the Department of Cardiology of the 904th Hospital of Joint Logistic Support Force of People's Liberation Army of China from 2016 to 2018 were selected and divided into control group and STEMI group. The demographic data, blood lipid level, laboratory indicators of blood and GDF11 level were collected. Logistic regression analysis screened out independent correlated factors for the occurrence of STEMI. Spearman correlation analysis clarified the correlation of each indicator with the SYNTAX or Gensini scores. A nomogram risk prediction model for the risk of STEMI occurrence and the receiver operating characteristic curve was used to compare the prediction efficiency of each model. Results: A total of 367 patients were enrolled, divided into control group (n=172) and STEMI group (n=195), age (66.5±11.8), male 222 (60.49%). The serum GDF11 level of STEMI group was significantly lower than that of the control group (36.20 (16.60, 70.75) µg/L vs. 85.00 (53.93, 117.10) µg/L, P<0.001). The results of multivariate logistic regression analysis showed serum GDF11(OR=0.98, 95%CI: 0.97-0.99) and traditional independent risk factors such as smoking, diabetes, C-reactive protein, homocysteine, lipoprotein (a) and apolipoprotein A1/B were independent correlate factors for the occurrence of STEMI (P<0.05). Spearman correlation analysis showed that serum GDF11 was negatively correlated with SYNTAX score and Gensini score (P<0.05). The nomogram model constructed by serum GDF11 combined with traditional independent risk factors (AUC=0.85, 95%CI: 0.81-0.89) had better predictive value for the occurrence of STEMI than the traditional nomogram model constructed by independent risk factors(AUC=0.80, 95%CI:0.75-0.84) or serum GDF11 (AUC=0.76, 95%CI: 0.72-0.81), all P<0.01. Conclusions: Serum GDF11 is an independent correlate factor in the occurrence of STEMI and is negatively correlated with the severity of coronary artery lesions in patients with STEMI. The nomogram model constructed based on GDF11 combined with traditional risk factors can be a good predictor for the occurrence of STEMI.
Subject(s)
Coronary Artery Disease , Myocardial Infarction , Percutaneous Coronary Intervention , ST Elevation Myocardial Infarction , Humans , Male , Bone Morphogenetic Proteins/blood , Bone Morphogenetic Proteins/chemistry , Coronary Artery Disease/diagnosis , Coronary Artery Disease/metabolism , Cross-Sectional Studies , Growth Differentiation Factors/blood , Growth Differentiation Factors/chemistry , Myocardial Infarction/blood , Myocardial Infarction/metabolism , Retrospective Studies , Risk Factors , ST Elevation Myocardial Infarction/blood , ST Elevation Myocardial Infarction/metabolismABSTRACT
Annually, the frequency of morbidity in depression has increased progressively in response to life stressors, and there is an increasing trend toward younger morbidity. The pathogenesis of depression is complicated and includes factors such as genetic inheritance and variations in physiological functions induced by various environmental factors. Currently, drug therapy has wide adaptability in clinical practice and plays an important role in the treatment of patients with mild depression. However, the therapeutic effects of most antidepressants are typically not significant and are associated with considerable adverse effects and addiction. Therefore, it is imperative to identify the deeper mechanisms of depression and search for alternative drug targets. Growth differentiation factor 11 (GDF11) is described as an anti-ageing molecule that belongs to a member of the transforming growth factor ß family. Additionally, the latest research findings suggested that GDF11 positively regulates neurogenesis and enhances neuronal activity, thereby attenuating depression-like behaviours. Although an increasing number of studies have focused on the multiple functions of GDF11 in skeletal dysplasia and carcinogenesis, its precise mechanism of action in depression remains unknown. Thus, in this review, we discuss the role of GDF11 and its mechanistic pathways in the pathogenesis of depression to develop novel therapies for depression.
Subject(s)
Depression , Growth Differentiation Factors , Humans , Depression/drug therapy , Growth Differentiation Factors/genetics , Growth Differentiation Factors/metabolism , Growth Differentiation Factors/pharmacology , Transforming Growth Factor beta , Aging , Bone Morphogenetic ProteinsABSTRACT
Acute myeloid leukemia (AML) is a hematologic malignancy characterized by the proliferation of CD34 positive self-renewing malignant hematopoietic stem cells. Previous studies have shown that the transforming growth factor beta (TGFß) pathway plays a role in AML pathogenesis, especially by affecting the microenvironment. Growth differentiation factor 11 (GDF11) is a member of the TGFß superfamily, involved in embryological development and known as rejuvenating factor. In this study, our aim was to determine the serum GDF11 level in patients with AML, to compare it with the control group, to determine its relationship with follistatin, vimentin, and E-cadherin levels, and to determine whether GDF11 influences AML prognosis. Serum GDF11, vimentin, follistatin, and E-cadherin levels of newly diagnosed or relapsed/refractory AML patients and age- and gender-matched control group were measured by enzyme-linked immunosorbent assay. Serum GDF11 level was higher in the patient group (263.87 ± 126.54 ng/L) compared to the control group (211.54 ± 61.47 ng/L; p = 0.035). GDF11 level did not change according to age, gender, hemoglobin level, and bone marrow blast rate. No correlation was found between GDF11 level, response rates, and survival status of the patients. A positive correlation was detected between GDF11, E-cadherin, and vimentin levels. As a conclusion, increased serum GDF11 levels in AML patients may be linked to the regeneration ability of leukemic stem cells. There is a need for studies investigating GDF11 expression in myeloblasts.
Subject(s)
Follistatin , Leukemia, Myeloid, Acute , Humans , Vimentin , Leukemia, Myeloid, Acute/pathology , Prognosis , Transforming Growth Factor beta , Growth Differentiation Factors , Cadherins , Tumor Microenvironment , Bone Morphogenetic ProteinsABSTRACT
Diabetic cardiomyopathy remains a formidable health challenge with a high mortality rate and no targeted treatments. Growth differentiation factor 11 (GDF11) has shown promising effects on cardiovascular diseases; however, its role and the underlying mechanism in regulating diabetic cardiomyopathy remain unclear. In this study, we developed mouse models of diabetic cardiomyopathy using leptin receptor-deficient (db/db) mice and streptozocin-induced C57BL/6 mice. The diabetic cardiomyopathy model mice exhibited apparent structural damage in cardiac tissues and a significant increase in the expression of apoptosis-related proteins. Notably, we observed a significant decreased expression of GDF11 in the myocardium of mice with diabetic cardiomyopathy. Moreover, GDF11 cardiac-specific knock-in mice (transgenic mice) exhibited improved cardiac function and reduced apoptosis. Moreover, exogenous administration of GDF11 mitigated high glucose-induced cardiomyocyte apoptosis. Mechanistically, we demonstrated that GDF11 alleviated high glucose-induced cardiomyocytes apoptosis by inhibiting the activation of the alkylation repair homolog 5 (ALKBH5)-forkhead box group O3a (FOXO3)-cerebellar degeneration-related protein 1 transcript (CDR1as)/Hippo signaling pathway. Consequently, this novel mechanism effectively counteracted myocardial cell apoptosis, providing valuable insights into potential therapeutic strategies for clinical diabetic cardiomyopathy.
Subject(s)
Diabetic Cardiomyopathies , Myocytes, Cardiac , Mice , Animals , Myocytes, Cardiac/metabolism , Diabetic Cardiomyopathies/chemically induced , Diabetic Cardiomyopathies/metabolism , Hippo Signaling Pathway , Mice, Inbred C57BL , Growth Differentiation Factors/genetics , Growth Differentiation Factors/metabolism , Growth Differentiation Factors/pharmacology , Glucose/pharmacology , Glucose/metabolism , Apoptosis/geneticsABSTRACT
Defining next-generation immune therapeutics for the treatment of sepsis will involve biomarker-based therapeutic decision-making. Bone morphogenetic protein 9 (BMP9) is a cytokine in the transforming growth factor-ß superfamily. Here, circulating BMP9 concentrations were quantified in two independent cohorts of patients with sepsis. Decreased concentrations of serum BMP9 were observed in the patients with sepsis at the time of admission as compared with healthy controls. Concentrations of BMP9 at the time of admission were also associated with 28-day mortality, because patients with sepsis at a higher risk of death had lower BMP9 concentrations. The mechanism driving the contribution of BMP9 to host immunity was further investigated using in vivo murine sepsis models and in vitro cell models. We found that BMP9 treatment improved outcome in mice with experimental sepsis. BMP9-treated mice exhibited increased macrophage influx into the peritoneal cavity and more efficient bacterial clearance than untreated mice. In vitro, BMP9 promoted macrophage recruitment, phagocytosis, and subsequent bacterial killing. We further found that deletion of the type 1 BMP receptor ALK1 in macrophages abolished BMP9-mediated protection against polymicrobial sepsis in vivo. Further experiments indicated that the regulation of macrophage activation by the BMP9-ALK1 axis was mainly mediated through the suppressor of mother against decapentaplegic 1/5 signaling pathway. Together, these results suggest that BMP9 can both serve as a biomarker for patient stratification with an independent prognostic value and be developed as a host-directed therapy for sepsis.
Subject(s)
Growth Differentiation Factor 2 , Sepsis , Humans , Animals , Mice , Growth Differentiation Factor 2/metabolism , Growth Differentiation Factors/metabolism , Bone Morphogenetic Proteins/metabolism , Prognosis , Signal TransductionABSTRACT
BACKGROUND: Cytoplatin (CDDP) is a standard treatment for triple-negative breast cancer (TNB), but patient resistance to CDDP limits its efficacy. A growing study confirms that microRNAs (miRNAs) are significantly important in breast cancer, especially TNBC. This research was carried out to examine the function of miR-106b-5p in CDDP resistance of TNBC as well as the downstream mechanism. METHODS: The miR-106b-5p and growth-differentiation factor 11 (GDF11) expressions in the tissues from TNBC patients and CDDP-treated TNBC cell lines were measured by RT-qPCR. Thereafter, cell proliferation and migration in the presence of CDDP treatment were evaluated via CCK-8 and Transwell assays in the TNBC cells. A xenograft mice model was also established to verify the miR-106b-5p silencing effect on the growth of CDDP resistance TNBC cells in vivo. Luciferase reporter experiments were performed to predict the relationship between miR-106b-5p and GDF11 expression. RESULTS: The results showed that miR-106b-5p was upregulated in the TNBC tumor cells and TNBC cells treated with CDDP and knockdown of this caused inhibition of the TNBC cell lines' proliferation, migration and suppressed the growth of the TNBC xenografted tumors, in the presence of CDDP treatment. In addition, it was observed that miR-106b-5p can bind to GDF11; as a result in the TNBC tissues and CDDP-treated TNBC cell lines the down-regulation of GDF11 was observed. Moreover, GDF11 silencing promoted CDDP-treated TNBC cell lines' proliferation and migration and reversed the interference effect of miR-106b-5p. CONCLUSIONS: MiR-106b-5p was upregulated in TNBC and this upregulation may promote CDDP resistance of the TNBC cells by targeting GDF11 and inhibiting its expression.
Subject(s)
MicroRNAs , Triple Negative Breast Neoplasms , Animals , Humans , Mice , Bone Morphogenetic Proteins/metabolism , Cell Line, Tumor , Cell Movement , Cell Proliferation , Cisplatin/pharmacology , Gene Expression Regulation, Neoplastic , Growth Differentiation Factors/metabolism , MicroRNAs/genetics , MicroRNAs/metabolism , Triple Negative Breast Neoplasms/drug therapy , Triple Negative Breast Neoplasms/geneticsABSTRACT
BACKGROUND: Heterochronic parabiosis has identified growth differentiation factor (GDF)-11 as a potential means of cardiac rejuvenation, but findings have been inconsistent. A major barrier has been lack of assay specificity for GDF-11 and its homolog GDF-8. METHODS: We tested the hypothesis that GDF-11 and GDF-8, and their major antagonists follistatin and follistatin-like (FSTL)-3, are associated with incident heart failure (HF) and its subtypes in elders. Based on validation experiments, we used liquid chromatography-tandem mass spectrometry to measure total serum GDF-11 and GDF-8, along with follistatin and FSTL-3 by immunoassay, in 2 longitudinal cohorts of older adults. RESULTS: In 2 599 participants (age 75.2â ±â 4.3) followed for 10.8â ±â 5.6 years, 721 HF events occurred. After adjustment, neither GDF-11 (HR per doubling: 0.93 [0.67, 1.30]) nor GDF-8 (HR: 1.02 per doubling [0.83, 1.27]) was associated with incident HF or its subtypes. Positive associations with HF were detected for follistatin (HR: 1.15 [1.00, 1.32]) and FLST-3 (HR: 1.38 [1.03, 1.85]), and with HF with preserved ejection fraction for FSTL-3 (HR: 1.77 [1.03, 3.02]). (All HRs per doubling of biomarker.) FSTL-3 associations with HF appeared stronger at higher follistatin levels and vice versa, and also for men, Blacks, and lower kidney function. CONCLUSIONS: Among older adults, serum follistatin and FSTL-3, but not GDF-11 or GDF-8, were associated with incident HF. These findings do not support the concept that low serum levels of total GDF-11 or GDF-8 contribute to HF late in life, but do implicate transforming growth factor-ß superfamily pathways as potential therapeutic targets.
Subject(s)
Bone Morphogenetic Proteins , Growth Differentiation Factors , Heart Failure , Myostatin , Aged , Humans , Male , Biomarkers , Follistatin , Growth Differentiation Factor 15 , Heart Failure/blood , Heart Failure/epidemiology , Myostatin/blood , Bone Morphogenetic Proteins/blood , Growth Differentiation Factors/bloodABSTRACT
Growth differentiation factor 11 (GDF11) is one of the important factors in the pathophysiological process of animals. It is widely expressed in many tissues and organs of animals, showing its wide biological activity and potential application value. Previous research has demonstrated that GDF11 has a therapeutic effect on various diseases, such as anti-myocardial aging and anti-tumor. This has not only sparked intense interest and enthusiasm among academics but also spurred some for-profit businesses to attempt to develop GDF11 as a medication for regenerative medicine or anti-aging application. Currently, Sotatercept, a GDF11 antibody drug, is in the marketing application stage, and HS-235 and rGDF11 are in the preclinical research stage. Therefore, we believe that figuring out which cells GDF11 acts on and its current problems should be an important issue in the scientific and commercial communities. Only through extensive, comprehensive research and discussion can we better understand the role and potential of GDF11, while avoiding unnecessary risks and misinformation. In this review, we aimed to summarize the role of GDF11 in different cells and its current controversies and challenges, providing an important reference for us to deeply understand the function of GDF11 and formulate more effective treatment strategies in the future.
Subject(s)
Cells , Growth Differentiation Factors , Humans , Animals , Growth Differentiation Factors/metabolism , Growth Differentiation Factors/therapeutic use , Cells/metabolism , Biomarkers , Neoplasms/therapy , Cardiomyopathies/therapy , Inflammation/therapyABSTRACT
Growth differentiation factor 11 (GDF11) is reported as a member of TGF-ß superfamily, which plays a key negative role in various tissue inflammation. However, the specific effect of GDF11 on infectious acute liver injury remains unknown. The current study is designed to certify the role of GDF11 both in LPS-induced RAW 264.7 cell line and rodent model of acute liver injury (ALI) and further investigate its molecular mechanism of inflammatory regulation. In vitro, LPS was used to stimulate the inflammatory activation of RAW 264.7 cells and then recombinant GDF11 (rGDF11) was used to treat the cells. In vivo, we injected LPS and rGDF11 in abdomen of mouse. The inflammatory indexes, GDF11 level, NLRP3 level, liver tissue injury, and liver function were examined using qRT-PCR, western blot, ELISA, IHC, IF and HE staining, respectively. Supplement of GDF11 protected the histology and function of liver tissue in LPS-induced ALI mice, in which the level of AST, ALT and TBiL associated with tissue damage were reduced after ALI. Moreover, increased GDF11 in RAW 264.7 cells and ALI mice reduced the expressions of COX-2, TNF-α, IL-1ß, and IL-6 via inhibiting NLRP3 inflammasome activation, suggesting the anti-inflammatory role of GDF11 in ALI. Besides, owing to the protective role of GDF11, the apoptotic degree in liver after LPS insult was attenuated, such as the reduced c-caspase-3 and annexin-V expressions. The results indicate that overexpression of GDF11 plays an antagonistic role in LPS-induced inflammatory response after ALI. Therefore, GDF11 may become a promising target for preventing infectious acute liver injury.
Subject(s)
Chemical and Drug Induced Liver Injury, Chronic , Growth Differentiation Factors , Inflammasomes , NLR Family, Pyrin Domain-Containing 3 Protein , Animals , Mice , Growth Differentiation Factors/genetics , Inflammasomes/metabolism , Inflammation , Lipopolysaccharides , Mice, Inbred C57BL , NLR Family, Pyrin Domain-Containing 3 Protein/genetics , NLR Family, Pyrin Domain-Containing 3 Protein/metabolismABSTRACT
Growth differentiation factor-15 (GDF15) is a stress-activated cytokine that regulates cell growth and inflammatory and stress responses. We previously reported the role and regulation of GDF15 in pituitary corticotrophs. Dexamethasone increases Gdf15 gene expression levels and production. GDF15 suppresses adrenocorticotropic hormone synthesis in pituitary corticotrophs and subsequently mediates the negative feedback effect of glucocorticoids. Here, we analyzed corticotropin-releasing factor (Crf) promoter activity in hypothalamic 4B cells transfected with promoter-driven luciferase reporter constructs. The effects of time and GDF15 concentration on Crf mRNA levels were analyzed using quantitative real-time polymerase chain reaction. Glial cell-derived neurotrophic factor family receptor α-like (GFRAL) protein is expressed in 4B cells. GDF15 increased Crf promoter activity and Crf mRNA levels in 4B cells. The protein kinase A and C pathways also contributed to the GDF15-induced increase in Crf gene expression. GDF15 stimulates GFRAL, subsequently increasing the phosphorylation of AKT, an extracellular signal-related kinase, and the cAMP response element-binding protein. Therefore, GDF15-dependent pathways may be involved in regulating Crf expression under stressful conditions in hypothalamic cells.
Subject(s)
Corticotropin-Releasing Hormone , Growth Differentiation Factor 15 , Hypothalamus , Corticotropin-Releasing Hormone/genetics , Corticotropin-Releasing Hormone/metabolism , Growth Differentiation Factors/genetics , Growth Differentiation Factors/metabolism , Growth Differentiation Factors/pharmacology , Hypothalamus/drug effects , Hypothalamus/metabolism , Promoter Regions, Genetic , Receptors, Corticotropin-Releasing Hormone/genetics , Receptors, Corticotropin-Releasing Hormone/metabolism , RNA, Messenger/metabolism , Animals , Rats , Growth Differentiation Factor 15/metabolism , Growth Differentiation Factor 15/pharmacology , HumansABSTRACT
As a major neuron type in the brain, the excitatory neuron (EN) regulates the lifespan in C. elegans. How the EN acquires senescence, however, is unknown. Here, we show that growth differentiation factor 11 (GDF11) is predominantly expressed in the EN in the adult mouse, marmoset and human brain. In mice, selective knock-out of GDF11 in the post-mitotic EN shapes the brain ageing-related transcriptional profile, induces EN senescence and hyperexcitability, prunes their dendrites, impedes their synaptic input, impairs object recognition memory and shortens the lifespan, establishing a functional link between GDF11, brain ageing and cognition. In vitro GDF11 deletion causes cellular senescence in Neuro-2a cells. Mechanistically, GDF11 deletion induces neuronal senescence via Smad2-induced transcription of the pro-senescence factor p21. This work indicates that endogenous GDF11 acts as a brake on EN senescence and brain ageing.
Subject(s)
Caenorhabditis elegans , Growth Differentiation Factors , Adult , Mice , Humans , Animals , Caenorhabditis elegans/metabolism , Growth Differentiation Factors/genetics , Growth Differentiation Factors/metabolism , Aging/genetics , Brain/metabolism , Neurons/metabolism , Bone Morphogenetic ProteinsABSTRACT
Platelet-rich plasma (PRP) has gained significant attention in the field of regenerative medicine due to its potential therapeutic applications. However, few studies have reported the components, especially anti-ageing-related components, of PRP derived from umbilical cord blood (UCB). It is essential to understand the influence of age on the composition and efficacy of PRP to optimize its clinical use. The present study compared the concentrations of bioactive components in PRP from healthy female adults and UCB-derived PRP. PRP was obtained from blood samples from females in four age groups (12 per group): neonates (UCB donors) and adults aged 18-25, 26-45, and 46-65 years, respectively. The concentrations of epidermal growth factor, basic fibroblast growth factor-2 (FGF-2), insulin-like growth factor-1, platelet-derived growth factor-AA (PDGF-AA), PDGF-AB/BB, vascular endothelial growth factor A, RANTES, TIMP-1, TIMP-2, GDF11, and clusterin and activity of superoxide dismutase, catalase, and glutathione peroxidase (GPx) in the PRP samples were determined and compared among groups. Pairwise comparisons between the groups showed statistically significant differences in the concentrations of some bioactive components of PRP, such as FGF-2, PDGF-AB/BB, and clusterin, and GPx activity. UCB-derived PRP contains various active ingredients such as VEGF-A, CAT activity, and TIMP-2. Contrary to expectations, UCB-derived PRP did not show higher concentrations of the anti-ageing protein GDF11. Because UCB is a rich source of bioactive components with low immunogenicity, its use in PRP preparation is an important research direction for future studies.
Subject(s)
Platelet-Rich Plasma , Vascular Endothelial Growth Factor A , Infant, Newborn , Humans , Adult , Female , Adolescent , Young Adult , Clusterin , Tissue Inhibitor of Metalloproteinase-2 , Fetal Blood , Fibroblast Growth Factor 2 , Becaplermin , Bone Morphogenetic Proteins , Growth Differentiation FactorsABSTRACT
Growth differentiation factor 11 (GDF11) is a putative systemic rejuvenation factor. In this study, we characterized the mechanism by which GDF11 reversed aging of mesenchymal stem cells (MSCs). In culture, aged MSCs proliferate slower and are positive for senescence markers senescence-associated ß-galactosidase and P16ink4a . They have shortened telomeres, decreased GDF11 expression, and reduced osteogenic potential. GDF11 can block MSC aging in vitro and reverse age-dependent bone loss in vivo. The antiaging effect of GDF11 is via activation of the Smad2/3-PI3K-AKT-mTOR pathway. Unexpectedly, GDF11 also upregulated a DNA demethylase Tet2, which served as a key mediator for GDF11 to autoregulate itself via demethylation of the GDF11 promoter. Mutation of Tet2 facilitates MSC aging by blocking GDF11 expression. Mutagenesis of Tet2-regulated CpG sites also blocks GDF11 expression, leading to MSC aging. Together, a novel mutual regulatory relationship between GDF11 and an epigenetic factor Tet2 unveiled their antiaging roles.