Growth differentiation factor 11 promotes macrophage polarization towards M2 to attenuate myocardial infarction via inhibiting Notch1 signaling pathway

Background:Myocardial infarctions(MI)is a major threat to human health especially in people exposed to cold environment.The polarization of macrophages towards different functional phenotypes(M1 macrophages and M2 macrophages)is closely related to MI repairment.The growth differentiation factor 11(GDF11)has been reported to play a momentous role in inflammatory associated diseases.In this study,we examined the regulatory role of GDF11 in macrophage polarization and elucidated the underlying mechanisms in MI.Methods:In vivo,the mice model of MI was induced by permanent ligation of the left anterior descending coronary artery(LAD),and mice were randomly divided into the sham group,MI group,and MI+GDF11 group.The protective effect of GDF11 on myocardial infarction and its effect on macrophage polarization were verified by echocardiography,triphenyl tetrazolium chloride staining and immunofluorescence staining of heart tissue.In vitro,based on the RAW264.7 cell line,the effect of GDF11 in promoting macrophage polarization toward the M2 type by inhibiting the Notch1 Signaling pathway was validated by qRT-PCR,Western blot,and flow cytometry.Results:We found that GDF11 was significantly downregulated in the cardiac tissue of MI mice.And GDF11 supplementation can improve the cardiac function.Moreover,GDF11 could reduce the proportion of M1 macrophages and increase the accumulation of M2 macrophages in the heart tissue of MI mice.Furthermore,the cardioprotective effect of GDF11 on MI mice was weakened after macrophage clearance.At the cellular level,application of GDF11 could inhibit the expression of M1 macrophage(classically activated macrophage)markers iNOS,interleukin(IL)-1β,and IL-6 in a dose-dependent manner.In contrast,GDF11 significantly increased the level of M2 macrophage markers including IL-10,CD206,arginase 1(Arg1),and vascular endothelial growth factor(VEGF).Interestingly,GDF11 could promote M1 macrophages polarizing to M2 macrophages.At the molecular level,GDF11 significantly down-regulated the Notch1 signaling pathway,the activation of which has been demonstrated to promote M1 polarization in macrophages.Conclusions:GDF11 promoted macrophage polarization towards M2 to attenuate myocardial infarction via inhibiting Notch1 signaling pathway.

Porcine growth differentiation factor 9 gene polymorphisms and their associations with litter size

Growth differentiation factor 9 （GDF9） is expressed in oocytes and is thought to be required for ovarian folliculogenesis. Given this function, GDF9 may be considered as a candidate gene controlling pig ovulate rate. In this study, the complete coding sequence was cloned （encoding a 444 amino acid）, intron sequence and partial 5＇-UTR of pig GDF9. RT-PCR results showed that GDF9 mRNA is expressed in a wide range of tissues of the ruttish Erhualian pig. The expression levels of GDF9 mRNA in pituitary, ovary, uterus and oviduct are higher in the Erhualian pigs than those in Duroc pigs, especially in pituitary with a significant difference （P 〈 0.05）. Comparative sequencing revealed 12 polymorphisms, including 8 single nucleotide polymorphisms （SNPs） and one 314 bp indel in noncoding regions, and the other 3 SNPs in coding regions. Four polymorphisms, G359C, C1801T, T1806C and 314 bp indel, were developed as markers for further use in population variation and association studies. The G359C polymorphism segregates only in Chinese native pigs, Erhualian and Dahuabai, on the contrary, 314 bp indel segregates only in Duroc and Landrace. C1801T and T1806C sites seem to be completely linked and segregate in Erhualian, Dahuabai and Landrace. In a word, GDF9 may be not associated with pig litter size in extensive populations as per the studies of allele distributions of the four polymorphisms and pilot association in four breeds.

Significance of 125I radioactive seed implantation on growth differentiation factor and programmed death receptor-1 during treatment of oral cancer

BACKGROUND Oral cancer(OC)is the most common malignant tumor in the oral cavity,and is mainly seen in middle-aged and elderly men.At present,OC is mainly treated clinically by surgery or combined with radiotherapy and chemotherapy;but recently,more and more studies have shown that the stress trauma caused by surgery and the side effects of radiotherapy and chemotherapy seriously affect the prognosis of patients.AIM To determine the significance of 125I radioactive seed implantation on growth differentiation factor 11(GDF11)and programmed death receptor-1(PD-1)during treatment of OC.METHODS A total of 184 OC patients admitted to The Second Affiliated Hospital of Jiamusi University from May 2015 to May 2017 were selected as the research subjects for prospective analysis.Of these patients,89 who received 125I radioactive seed implantation therapy were regarded as the research group(RG)and 95 patients who received surgical treatment were regarded as the control group(CG).The clinical efficacy,incidence of adverse reactions and changes in GDF11 and PD-1 before treatment(T0),2 wk after treatment(T1),4 wk after treatment(T2)and 6 wk after treatment(T3)were compared between the two groups.RESULTS The efficacy and recurrence rate in the RG were better than those in the CG(P<0.05),while the incidence of adverse reactions and survival rate were not different.There was no difference in GDF11 and PD-1 between the two groups at T0 and T1,but these factors were lower in the RG than in the CG at T2 and T3(P<0.05).Using receiver operating characteristic(ROC)curve analysis,GDF11 and PD-1 had good predictive value for efficacy and recurrence(P<0.001).CONCLUSION 125I radioactive seed implantation has clinical efficacy and can reduce the recurrence rate in patients with OC.This therapy has marked potential in clinical application.The detection of GDF11 and PD-1 in patients during treatment showed good predictive value for treatment efficacy and recurrence in OC patients,and may be potential targets for future OC treatment.

Growth differentiation factor 5:a neurotrophic factor with neuroprotective potential in Parkinson’s disease

Parkinson’s disease is the most common movement disorder worldwide,affecting over 6 million people.It is an age-related disease,occurring in 1%of people over the age of 60,and 3%of the population over 80 years.The disease is characterized by the progressive loss of midbrain dopaminergic neurons from the substantia nigra,and their axons,which innervate the striatum,resulting in the characteristic motor and non-motor symptoms of Parkinson’s disease.This is paralleled by the intracellular accumulation ofα-synuclein in several regions of the nervous system.Current therapies are solely symptomatic and do not stop or slow disease progression.One promising disease-modifying strategy to arrest the loss of dopaminergic neurons is the targeted delivery of neurotrophic factors to the substantia nigra or striatum,to protect the remaining dopaminergic neurons of the nigrostriatal pathway.However,clinical trials of two well-established neurotrophic factors,glial cell line-derived neurotrophic factor and neurturin,have failed to meet their primary end-points.This failure is thought to be at least partly due to the downregulation byα-synuclein of Ret,the common co-receptor of glial cell line-derived neurorophic factor and neurturin.Growth/differentiation factor 5 is a member of the bone morphogenetic protein family of neurotrophic factors,that signals through the Ret-independent canonical Smad signaling pathway.Here,we review the evidence for the neurotrophic potential of growth/differentiation factor 5 in in vitro and in vivo models of Parkinson’s disease.We discuss new work on growth/differentiation factor 5’s mechanisms of action,as well as data showing that viral delivery of growth/differentiation factor 5 to the substantia nigra is neuroprotective in theα-synuclein rat model of Parkinson’s disease.These data highlight the potential for growth/differentiation factor 5 as a disease-modifying therapy for Parkinson’s disease.

Elevated serum growth differentiation factor 15 in multiple system atrophy patients:A case control study

BACKGROUND 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.AIM 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.METHODS A case-control study was conducted, including 49 MSA patients, 50 PD patients and 50 healthy controls. Serum GDF15 levels were measured by human enzymelinked 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 analysiswas used to evaluate the diagnostic value of GDF15, especially for the differential diagnosis between MSA and PD.RESULTS 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/m L, sensitivity: 85.7%, specificity: 88.0%;cutoff: 1075.91 pg/m L, sensitivity:51.0%, specificity: 96.0%;respectively).CONCLUSION Serum GDF15 levels are significantly higher in MSA patients and provide suggestions on the etiology of MSA.

Growth differentiation factor 15 as an emerging novel biomarker in SARS-CoV-2 infection

BACKGROUND Growth differentiation factor(GDF)-15 is a member of a transforming growth factor-βcytokine superfamily that regulates metabolism and is released in response to inflammation,hypoxia and tissue injury.It has evolved as one of the most potent cytokines for predicting the severity of infections and inflammatory conditions,such as severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)infection.AIM To investigate the utility of GDF-15 in predicting the severity of SARS-CoV-2 infection.METHODS PubMed,Reference Citation Analysis,CNKI,and Goggle Scholar were explored by using related MeSH keywords and data such as the first author’s name,study duration,type and place of study,sample size and subgroups of participants if any,serum/plasma GDF-15 level in pg/mL,area under the curve and cut-off value in receiver operating characteristic analysis,method of measurement of GDF-15,and the main conclusion were extracted.RESULTS In all studies,the baseline GDF-15 level was elevated in SARS-CoV-2-infected patients,and it was significantly associated with severity,hypoxemia,viral load,and worse clinical consequences.In addition,GDF-15 levels were correlated with C-reactive protein,D-dimer,ferritin and procalcitonin,and it had superior discriminatory ability to detect severity and in-hospital mortality of SARS-CoV-2 infection.Hence,GDF-15 might be used to predict the severity and prognosis of hospitalized patients with SARS-CoV-2.CONCLUSION Serial estimation of GDF-15 levels in hospitalized patients with SARS-CoV-2 infection appeared to have useful prognostic value and GDF-15 can be considered a clinically prominent sepsis biomarker for SARS-CoV-2 infection.

Chondrogenic differentiation of human bone mesenchymal stem cells treated with growth differentiation factor 5 under hypoxia

Objective To explore the feasibility and effectiveness of the self-assembly cartilage tissue engineered with chondrogenically differentiated human bone mesenchymal stem cells (hBMCs) induced by growth differentiation factor-5 (GDF-5)

Association between plasma growth differentiation factor 15 levels and pre-eclampsia in China

Background Growth differentiation factor-15(GDF-15)is a stress response protein and is related to cardiovascular diseases(CVD).This study aimed to investigate the association between GDF-15 and pre-eclampsia(PE).Method The study involved 299 pregnant women,out of which 236 had normal pregnancies,while 63 participants had PE.Maternal serum levels of GDF-15 were measured by using enzyme-linked immunosorbent assay kits and then translated into multiple of median(MOM)to avoid the influence of gestational week at blood sampling.Logistic models were performed to estimate the association between GDF-15 MOM and PE,presenting as odd ratios(ORs)and 95%confidence intervals(CIs).Results MOM of GDF-15 in PE participants was higher compared with controls(1.588 vs.1.000,p<0.001).In the logistic model,pregnant women with higher MOM of GDF-15(>1)had a 4.74-fold(95%CI=2.23–10.08,p<0.001)increased risk of PE,adjusted by age,preconceptional body mass index,gravidity,and parity.Conclusions These results demonstrated that higher levels of serum GDF-15 were associated with PE.GDF-15 may serve as a biomarker for diagnosing PE.

Neurotrophic factors: from neurodevelopmental regulators to novel therapies for Parkinson's disease

Neuroprotection and neuroregeneration are two of the most promising disease-modifying ther- apies for the incurable and widespread Parkinson＇s disease. In Parkinson＇s disease, progressive degeneration of nigrostriatal dopaminergic neurons causes debilitating motor symptoms. Neurotrophic factors play important regulatory roles in the development, survival and maintenance of specific neuronal populations. These factors have the potential to slow down, halt or reverse the loss of nigrostriatal dopaminergic neurons in Parkinsoffs disease. Several neurotrophic fac- tors have been investigated in this regard. This review article discusses the neurodevelopmental roles and therapeutic potential of three dopaminergic neurotrophic factors： glial cell line-derived neurotrophic factor, neurturin and growth/differentiation factor 5.

GDF-15 Level Correlates with CMKLR1 and VEGF-A in Tumor-free Margin in Colorectal Cancer

Colorectal cancer(CRC)is the third most frequently diagnosed cancer worldwide,responsible for over 880000 deaths each year.Growth/differentiation factor 15(GDF-15)is reported to be a promising diagnostic and prognostic factor in CRC.It induces pleiotropic effects in tumor cells:proliferation,sternness,invasion and metastasis.Some studies indicate that GDF-15 may stimulate angiogenesis in malignant neoplasms.However,it has not been investigated in CRC yet.The aim of our study was to determine the level of GDF-15 and the concentrations of hypoxia-inducible factor-la(HIF-1α),VEGF-A and chemokine-like receptor 1(CMKLR1)in tumor and margin specimens of CRC in relation to histological grade and TNM staging.The study comprised 33 samples of tumor and margin tissues obtained from CRC patients.To assess the concentration of GDF-15,HIF-1α,VEGF-A and CMKLR1,commercially available enzyme-linked immunosorbent assay(ELISA)kits were used.We found significantly increased levels of GDF-15 and CMKLR1 in tumor tissue compared to margin tissue and higher concentrations of HIF-1α and VEGF-A in margin tissue than in tumor tissue.The levels of GDF-15 and HIF-1α were significantly correlated with VEGF-A and CMKLR1 in margin tissue.In CRC,the increased level of GDF-15 might stimulate angiogenesis through upregulation of HIF-1α,VEGF A and CMKLR1 expression.Our study is the first one to reveal the correlation between the levels of GDF-15 and CMKLR1 in CRC.The elevated levels of HIF-1α and VEGF-A in tumor-free margin tissues suggest that noncancer cells in the tumor microenvironment are an important source of proangiogenic factors.

Effect of growth and differentiation factor 6 on the tenogenic differentiation of bone marrow-derived mesenchymal stem cells

Background Recent studies showed that bone marrow-derived mesenchymal stem ceils （BMSCs） had risk of ectopic bone formation. In this study, we aimed to investigate the effect of growth and differentiation factor 6 （GDF-6） on the tenogenic differentiation of BMSCs in vitro, and then combined with small intestine submucous （SIS） to promote tendon regeneration in vivo. Methods The BMSCs were isolated from the green fluorescent protein （GFP） rats, and were characterized by multi-differentiation assays following our previous study protocol. BMSCs cultured with different concentrations of GDF-6, without growth factors served as control. After 2 weeks, mRNA expression and protein expression of tendon specific markers were examined by qRT-PCR and Western blotting to define an optimal concentration of GDF-6. Mann-Whitney U-test was used to compare the difference in relative mRNA expression among all groups; P 〈0.05 was regarded as statistically significant. The GDF-6 treated BMSCs combined with SIS were implanted in nude mice and SD rat acute patellar tendon injury model, the BMSCs combined with SIS served as control. After 12 and 4 weeks in nude mice and tendon injury model, the samples were collected for histology. Results After the BMSCs were treated with different concentration of GDF-6 for 2 weeks, the fold changes of the specific markers （Tenomodulin and Scleraxis） mRNA expression were significantly higher in GDF-6 （20 ng/ml） group （P 〈_0.05）, which was also confirmed by Western blotting result. The BMSCs became parallel in orientation after GDF-6 （20 ng/ml） treatment, but the BMSCs in control group were randomly oriented. The GDF-6 （20 ng/ml） treated BMSCs were combined with SIS, and were implanted in nude mice for 12 weeks, the histology showed neo-tendon formation. In the SD rat patellar tendon window injury model, the histology also indicated the GDF-6 （20 ng/ml） treated BMSCs combined with SIS could promote tendon regeneration. Conclusions GDF-6 has tenogenic effect on the tenogenic differentiation of BMSCs, and GDF-6 （20 ng/ml） has better tenogenic effect compared to other concentrations. The GDF-6 （20 ng/ml） treated BMSCs combined with SIS can form neo-tendons and promote tendon regeneration.

Construction of Self-Assembled Cartilage Tissue from Bone Marrow Mesenchymal Stem Cells Induced by Hypoxia Combined with GDF-5

It is widely known that hypoxia can promote chondrogenesis of human bone marrow de- rived mesenchymal stem cells （hMSCs） in monolayer cultures. However, the direct impact of oxygen tension on hMSC differentiation in three-dimensional cultures is still unknown. This research was de- signed to observe the direct impact of oxygen tension on the ability of hMSCs to ＂self assemble＂ into tissue-engineered cartilage constructs, hMSCs were cultured in chondrogenic medium （CM） containing 100 ng/mL growth differentiation factor 5 （GDF-5） at 5% （hypoxia） and 21% （normoxia） 02 levels in monolayer cultures for 3 weeks. After differentiation, the cells were digested and employed in a self- assembly process to produce tissue-engineered constructs under hypoxic and normoxic conditions in vi- tro. The aggrecan and type ]I collagen expression, and type X collagen in the self-assembled con- structs were assessed by using immunofluorescent and immunochemical staining respectively. The methods of dimethylmethylene blue （DMMB）, hydroxyproline and PicoGreen were used to measure the total collagen content, glycosaminoglycan （GAG） content and the number of viable cells in each con- struct, respectively. The expression of type II collagen and aggrecan under hypoxic conditions was in- creased significantly as compared with that under normoxic conditions. In contrast, type X collagen expression was down-regulated in the hypoxic group. Moreover, the constructs in hypoxic group showed more significantly increased total collagen and GAG than in normoxic group, which were more close to those of the natural cartilage. These findings demonstrated that hypoxia enhanced chondro- genesis of in vitro, scaffold-free, tissue-engineered constructs generated using hMSCs induced by GDF-5. In hypoxic environments, the self-assembled constructs have a Thistological appearance and biochemical parameters similar to those of the natural cartilage.

Cardioprotective Effect of Growth Differentiation Factor 15 Against Isoproterenol-Induced Cardiomyocyte Apoptosis via Regulation of the Mitochondrial Fusion

Objective:Pressure overload-induced myocardial apoptosis is a critical pathologically initiated process leading to heart failure(HF).Growth differentiation factor 15(GDF15)dramatically increases during cardiac hypertrophy and dysfunction,but its functions and mechanisms are barely known.This study aims to elucidate the role and mechanism of GDF15 in HF.Methods:Between January 2017 and August 2018,57 patients diagnosed with chronic HF(aged>18 years,with left ventricular ejection fraction(LVEF)35%)and 57 non-HF patients(aged>18 years,LVEF>35%)were prospectively enrolled in this study based on the balance of the baseline characteristics.Other acute or chronic diseases and pregnant/lactating women were excluded.The serum concentrations of GDF15 were detected.Isoproterenol(ISO)-induced HF mouse model was established by pumping with ISO(30mg/(kg·day))for 4 weeks,and the GDF15 expression in serum and heart tissue was evaluated in vivo.Primary cardiomyocytes were cultured and treated with ISO to induce cardiomyocytes damage.The apoptosis of cardiomyocytes and the effect of GDF15 on ISO-induced cardiomyocytes injury was evaluated in vitro.Results:After adjusting the baseline characteristic,serum levels of GDF15 were significantly higher in HF subjects than in non-HF patients.Similarly,in the ISO-induced HF mouse model,the significant increase in GDF15 was associated with the process of HF in vivo.Moreover,the elevation of GDF15 occurred prior to heart remodeling in the ISO-induced HF mouse model.Furthermore,using primary cardiomyocytes,we demonstrated that the GDF15 was remarkably enhanced in serum from pathological HF patients and cardiac tissue from the ISO-induced mouse model.Reducing GDF15 exaggerated the ISO-induced cell apoptosis by blocking mitochondrial fusion and increasing oxidative stress.In contrast,the silence of GDF15 aggravated the ISO-induced cardiomyocytes damage.Conclusions:GDF15 acts as a protective factor against cardiomyocyte apoptosis by improving mitochondria fusion during HF.These findings indicate that GDF15 may be a potential therapeutic target for HF.

The energetics of cellular life transitions

Major life transitions are always difficult because change costs energy.Recent findings have demonstrated how mitochondrial oxidative phosphorylation(OxPhos)defects increase the energetic cost of living and that excessive integrated stress response(ISR)signaling may prevent cellular identity transitions during development.In this perspective,we discuss general bioenergetic principles of life transitions and the costly molecular processes involved in reprograming the cellular hardware/software as cells shift identity.The energetic cost of cellular differentiation has not been directly quantified,representing a gap in knowledge.We propose that the ISR is an energetic checkpoint evolved to(i)prevent OxPhos-deficient cells from engaging in excessively costly transitions and(ii)allow ISR-positive cells to recruit systemic energetic resources by signaling via GDF15 and the brain.