Cardiovascular Diseases ; Follistatin-Related Proteins ; physiology ; Humans

BACKGROUND: Follistatin-like 1 (FSTL1) plays both pro-inflammatory and anti-inflammatory roles in the inflammatory processes. We investigated whether serum FSTL1 could predict the current anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV)-specific indices. METHODS: We randomly selected 74 patients with AAV from a prospective and observational cohort of Korean patients with AAV. Clinical and laboratory data and AAV-specific indices were recorded. FSTL1 concentration was determined using the stored sera. The lowest tertile of the short-form 36-item health survey (SF-36) was defined as the current low SF-36. The cutoffs of serum FSTL1 for the current low SF-36 physical component summary (PCS) and SF-36 mental component summary (MCS) were extrapolated by the receiver operator characteristic curve. RESULTS: The median age was 62.5 years (55.4% were women). Serum FSTL1 was significantly correlated with SF-36 PCS (r =  - 0.374), SF-36 MCS (r = -0.377), and C-reactive protein (CRP) (r = 0.307), but not with Birmingham vasculitis activity score (BVAS). In the multivariable linear regression analyses, BVAS, CRP, and serum FSTL1 were independently associated with the current SF-36 PCS (β = -0.255, β = -0.430, and β = -0.266, respectively) and the current SF-36 MCS (β = -0.234, β =-0.229, and β = -0.296, respectively). Patients with serum FSTL1 ≥779.8 pg/mL and those with serum FSTL1 ≥841.6 pg/mL exhibited a significantly higher risk of having the current low SF-36 PCS and SF-36 MCS than those without (relative risk 7.583 and 6.200, respectively). CONCLUSION Serum FSTL1 could predict the current functional status in AAV patients.
Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis ; Female ; Follistatin ; Follistatin-Related Proteins ; Functional Status ; Humans ; Male ; Middle Aged ; Prospective Studies ; Severity of Illness Index

OBJECTIVE: To analyze and predict the effect of coronavirus infection on hematopoietic system and potential intervention drugs, and explore their significance for coronavirus disease 2019 (COVID-19). METHODS: The gene expression omnibus (GEO) database was used to screen the whole genome expression data related with coronavirus infection. The R language package was used for differential expression analysis and KEGG/GO enrichment analysis. The core genes were screened by PPI network analysis using STRING online analysis website. Then the self-developed apparent precision therapy prediction platform (EpiMed) was used to analyze diseases, drugs and related target genes. RESULTS: A database in accordance with the criteria was found, which was derived from SARS coronavirus. A total of 3606 differential genes were screened, including 2148 expression up-regulated genes and 1458 expression down-regulated genes. GO enrichment mainly related with viral infection, hematopoietic regulation, cell chemotaxis, platelet granule content secretion, immune activation, acute inflammation, etc. KEGG enrichment mainly related with hematopoietic function, coagulation cascade reaction, acute inflammation, immune reaction, etc. Ten core genes such as PTPRC, ICAM1, TIMP1, CXCR5, IL-1B, MYC, CR2, FSTL1, SOX1 and COL3A1 were screened by protein interaction network analysis. Ten drugs with potential intervention effects, including glucocorticoid, TNF-α inhibitor, salvia miltiorrhiza, sirolimus, licorice, red peony, famciclovir, cyclosporine A, houttuynia cordata, fluvastatin, etc. were screened by EpiMed plotform. CONCLUSION SARS coronavirus infection can affect the hematopoietic system by changing the expression of a series of genes. The potential intervention drugs screened on these grounds are of useful reference significance for the basic and clinical research of COVID-19.
COVID-19 ; Computational Biology ; Follistatin-Related Proteins ; Hematopoietic System ; Humans ; Pharmaceutical Preparations ; SARS-CoV-2

OBJECTIVETo investigate the change in the serum level of follistatin-like protein 1 (FSTL1) in children with chronic heart failure and its correlation with left ventricular remodeling.

METHODSA total of 45 children with chronic heart failure (CHF) between May 2014 and May 2015 were selected as the CHF group, among whom 21 had endocardial fibroelastosis (EFE) and 24 had dilated cardiomyopathy (DCM); another 30 healthy children were selected as the control group. Enzyme-linked immunosorbent assay was applied to measure the serum level of FSTL1. Radioimmunoassay was applied to measure N-terminal pro-brain natriuretic peptide, and echocardiography was applied to measure the indicators of left ventricular remodeling. The correlation between the serum level of FSTL1 and left ventricular remodeling was analyzed by Pearson correlation and Spearman′s rank correlation analysis.

RESULTSBefore treatment, the CHF group had a significantly higher serum level of FSTL1 than the control group (P<0.05), which gradually increased with aggravation of CHF (P<0.05). The serum level of FSTL1 showed no significant difference between the EFE and DCM groups (P=0.176). Serum level of FSTL1 was positively correlated with left ventricular end-diastolic diameter (r=0.485, P=0.001), left ventricular mass (r=0.322, P=0.031), left ventricular mass index (r=0.353, P=0.017), and N-terminal pro-brain natriuretic peptide (r=0.562 P<0.001), and was negatively correlated with left ventricular ejection fraction (r=-0.436, P=0.003) and left ventricular minor axis decurtation rate (r=-0.436, P=0.003).

CONCLUSIONSFSTL1 might take part in the left ventricular remodeling in children with CHF, and the serum level of FSTL1 can be used as an objective index for clinical diagnosis and severity assessment of CHF in children.

Child ; Child, Preschool ; Female ; Follistatin-Related Proteins ; blood ; Heart Failure ; blood ; diagnosis ; Humans ; Infant ; Male

OBJECTIVE: To study the influence and cloning of differentially expressed genes in human female normal myometrium and uterine leiomyoma tissue. METHODS: In this experiment, human uterus tissues (n=25) were taken for total RNA isolation by using Trizol reagent. Differential display was performed by using GeneFishingTM DEG Kit and processed to cDNA sequencing and gene cloning for Follistatin-like 1 (FSTL1). Data were analyzed with the image Master VDS software and statistical significance was defined as p<0.05 by paired t test results. RESULTS: FSTL1 mRNA expression level was significantly higher (p<0.05) in normal and adjacent normal myometrium tissues than uterine leiomyoma tissue of women in the reproductive age. Whereas in the menopausal age, FSTL1 mRNA expression level was significantly higher (p<0.05) in uterine leiomyoma than normal myometrium. There was no significant differences between uterine leiomyoma and adjacent normal myometrium. CONCLUSION: Although the mechanisms of FSTL1 gene were uncertain, FSTL1 seemed to play an important role in the growth of uterine leiomyoma, it also might be related to the regulation of uterine leiomyoma growth inhibiting factors by modulating Follistatin related protein gene (FLRG) system.
Animals ; Clone Cells* ; Cloning, Organism* ; DNA, Complementary ; Female ; Follistatin ; Humans ; Leiomyoma* ; Mice ; Myometrium* ; RNA ; RNA, Messenger* ; Uterus

Delivery of follistatin (FST) represents a promising strategy for both muscular dystrophies and diabetes, as FST is a robust antagonist of myostatin and activin, which are critical regulators of skeletal muscle and adipose tissues. FST is a multi-domain protein, and deciphering the function of different domains will facilitate novel designs for FST-based therapy. Our study aims to investigate the role of the N-terminal domain (ND) of FST in regulating muscle and fat mass in vivo. Different FST constructs were created and packaged into the adeno-associated viral vector (AAV). Overexpression of wild-type FST in normal mice greatly increased muscle mass while decreasing fat accumulation, whereas overexpression of an N terminus mutant or N terminus-deleted FST had no effect on muscle mass but moderately decreased fat mass. In contrast, FST-I-I containing the complete N terminus and double domain I without domain II and III had no effect on fat but increased skeletal muscle mass. The effects of different constructs on differentiated C2C12 myotubes were consistent with the in vivo finding. We hypothesized that ND was critical for myostatin blockade, mediating the increase in muscle mass, and was less pivotal for activin binding, which accounts for the decrease in the fat tissue. An in vitro TGF-beta1-responsive reporter assay revealed that FST-I-I and N terminus-mutated or -deleted FST showed differential responses to blockade of activin and myostatin. Our study provided direct in vivo evidence for a role of the ND of FST, shedding light on future potential molecular designs for FST-based gene therapy.
Activins ; Animals ; Follistatin* ; Genetic Therapy ; In Vitro Techniques ; Mice ; Muscle Fibers, Skeletal ; Muscle, Skeletal ; Muscular Dystrophies ; Myostatin ; Negotiating

Sonic hedgehog (Shh) has been known as an essential morphogen for the generation of motor neuron in developing spinal cord. However, motor neuron can be generated in Shh -/- ; Gli3 -/- or Gli2 -/- ; Gli3 -/- mutants although these mutants don't have Shh signaling. To find out the compensatory mechanism for the generation of motor neuron in Shh -/- ; Gli3 -/- mutant, we studied bone morphogenetic protein (BMP) antagonists including follistatin, flik and noggin, and retinoic acid signaling in this mutant. To study expressions of BMP antagonists, we performed in situ hybridization. To examine an activity of retinoic acid, we measured beta -galactosidase activity in retinoic acid response element (RARE) transgenic mouse. The expression of follistatin was reduced at both levels of forelimb and hindlimb in Shh -/- mutant compared to wild type embryo. It was restored at the level of forelimb but reduced at the level of hindlimb in Shh -/- ; Gli3 -/- mutant compared to wild type. The expression of flik was similar with wild type embryo at both levels of forelimb and hindlimb in Shh -/- mutant. The expression of flik was similar with wild type embryo at the level of forelimb however reduced in hindlimb level in Shh -/- ; Gli3 -/- mutant. The expression of noggin, a BMP antagonist, was increased in Shh -/- mutant. Activity of retinoic acid signaling was not affected in Shh -/- or Shh -/- ; Gli3 -/- mutants. From these results, we conclude that retinoic acid but not follistatin and flik, may be involved in the generation of motor neuron in Shh -/- ; Gli3 -/- mutant.
Animals ; Bone Morphogenetic Proteins ; Embryonic Structures ; Follistatin ; Forelimb ; Hedgehogs ; Hindlimb ; In Situ Hybridization ; Mice ; Mice, Transgenic ; Motor Neurons ; Response Elements ; Spinal Cord ; Tretinoin

OBJECTIVES: It has been identified a novel protein in porcine and bovine follicular fluid termed Gonadotropin Surge Inhibiting Factor (GnSIF) which inhibits GnRH-stimulated LH secretion by pituitary cells in culture. The purpose of this study was to investigate the production of GnSIF by porcine granulosa cell in vitro. MATERIALS AND METHODS: Granulosa cells were aspirated from different size of porcine follicles (1-3mm, 3-5mm, >6mm in diameter) and cultured in 24-well plates in Ham's F-12/DMEM at 500,000 cells/well for 24h. After plating, cells were washed and incubated in triplicate for 72h in DMEM/F-12 containing 2% FBS in the presence of 100ng/ml FSH and the media were collected. Granulosa cell-conditioned media were chromatographed on heparin-Sepharose to remove inhibin and follistatin, and assayed for GnSIF activity using a rat pituitary cell bioassay. Briefly, dispersed pituitary cells from adult female Sprague-Dawley rats were plated (500,000 cells/well) for 72h, washed, and incubated with granulosa cell-conditioned media in the presence of 10nM GnRH for 4h. The media were collected and assayed for LH by RIA. GnSIF activity is defined as the suppression of GnRH-stimulated LH secretion. RESULTS: Granulosa cell-conditioned media significantly inhibited GnRH-stimulated LH secretion by rat pituitary cells in vitro (69% of control, P<0.001, n=2 experiments). Preliminary data suggest that granulosa cells from small follicles (1-3mm) produce greater amounts of GnSIF than those obtained from larger follicles (>6mm). CONCLUSIONS: GnSIF activity is produced by porcine granulosa cells in vitro. Granulosa cell production of GnSIF, along with other gonadal proteins such as inhibin, follistatin, and activin may be an important component of the ovarian control of pituitary gonadotropin secretion.
Activins ; Adult ; Animals ; Biological Assay ; Female ; Follicular Fluid ; Follistatin ; Gonadotropin-Releasing Hormone ; Gonadotropins* ; Gonads ; Granulosa Cells* ; Humans ; Inhibins ; Rats ; Rats, Sprague-Dawley

Follicle stmulating hormone ( FSH ) consist of alpha and beta subunits, which are encoded by se-parate genes. Pituitary release of FSH appears to be regulated by the hypothalamic GnRH and the gonadal steroid hormones. In addition, inhibin and follistatin produced by the gonad have been known to inhibit FSH secretion selectively. However, little is known about their regulation of the biosynthesis of FSH subunits at transcriptional and posttranscriptional levels. In the pre-sent study, we studied the time course of changes in alpha and FSH beta subunit mRNA concentrati-ons after castration and the effects of ovarian steroids of changes in alpha and FSH beta subunit mRNA concentrations after castration and the effects of ovarian steroids on alpha and FSH beta subunit mRNA in ovariectomized rats in order to determine Whether FSH subunit synthesis is modulated at the pretranslational levels, and whether synthesis and secretion are differently regulated. Results are as follows : 1. The time course of the rise in the steady state alpha subunit and FSH beta subunit mRNA levels were observed after ovariectomy, which paralleled the increases in serum and pituitary FSH concentrations. The time course experiments revealed differences in the patterns of alpha and FSH beta subunit mRNA responses, the rise in FSH beta subunit mRNA levels being more pro- minent than the rise in alpha subunit mRNA. 2. FSH beta mRNA levels were negatively regulated by the single injection of progesterone but not by estradiol, suggesting that FSH beta subunit mRNA seemed to be more sensitive to ne-gative feedback by progesterone than estradiol. Similar results were obtained by the continuous treatment of ovarian steroids for 1~4 days, but inhibition was more prominent with continuous treatment. It is, therefore, concluded that estradiol and progesterone inhibit the synthesis of FSH at the pretranslational level by modulating the steady state levels of alpha and FSH beta subunit mRNA, progesterone effect being more promiment than that of estradiol and alpha and FSH beta subunit are regulated in a different manner.
Animals ; Castration ; Estradiol ; Female ; Follicle Stimulating Hormone* ; Follicle Stimulating Hormone, beta Subunit ; Follistatin ; Gonadal Steroid Hormones ; Gonadotropin-Releasing Hormone ; Gonads ; Inhibins ; Ovariectomy* ; Progesterone ; Rats* ; RNA, Messenger* ; Steroids

Objective: To screen the different expressed genes between osteosarcoma and normal osteoblasts, and find the key genes for the occurrence and development of osteosarcoma. Methods: The gene expression dataset GSE33382 of normal osteoblasts and osteosarcoma was obtained from Gene Expression Omnibus (GEO) database. The different expressed genes between normal osteoblasts and osteosarcoma were screened by limma package of R language, and the different expressed genes were analyzed by Kyoto encyclopedia of genes and genomes (KEGG) pathway enrichment analysis. The protein interaction network was constructed by the String database, and the network modules in the interaction network were screened by the molecular complex detection (MCODE) plug-in of Cytoscape software. The different expressed genes contained in the first three main modules screened by MCODE were analyzed by gene ontology (GO) using the BiNGO module of Cytoscape software. The MCC algorithm was used to screen the top 10 key genes in the protein interaction network. The gene expression and survival dataset GSE39055 of osteosarcoma was obtained from GEO database, and the survival analysis was performed by Kaplan-Meier method. The data of 48 patients with osteosarcoma treated in the First Affiliated Hospital of Fujian Medical University from January 2005 to December 2015 were selected for verification. The expression of STC2 protein in osteosarcoma was detected by immunohistochemical method, and the survival analysis was carried out combined with the clinical data of the patients. Results: A total of 874 different expressed genes were identified from GSE33382 dataset, including 402 down-regulated genes and 472 up-regulated genes. KEGG enrichment analysis showed that different expressed genes were mainly related to p53 signal pathway, glutathione metabolism, extracellular matrix receptor interaction, cell adhesion molecules, folate tolerance, and cell senescence. The top 10 key genes in the interaction network were GAS6, IL6, RCN1, MXRA8, STC2, EVA1A, PNPLA2, CYR61, SPARCL1 and FSTL3. STC2 was related to the survival rate of patients with osteosarcoma (P<0.05). The results showed that the expression of STC2 protein was related to tumor size and Enneking stage in 48 cases of osteosarcoma. The median survival time of 25 cases with STC2 high expression was 21.4 months, and that of 23 cases with STC2 low expression was 65.4 months. The survival rate of patients with high expression of STC2 was lower than that of patients with low expression of STC2 (P<0.05). Conclusions: Bioinformatics analysis can effectively screen the different expressed genes between osteosarcoma and normal osteoblasts. STC2 is one of the important predictors for the prognosis of osteosarcoma.
Bone Neoplasms/pathology* ; Computational Biology/methods* ; Follistatin-Related Proteins/genetics* ; Gene Expression Profiling/methods* ; Gene Expression Regulation, Neoplastic ; Humans ; Osteosarcoma/pathology*