Impact of Bariatric Surgery on metabolic health in a Uruguayan cohort and the emerging predictive role of FSTL1.

Obesity poses significant challenges, necessitating comprehensive strategies for effective intervention. Bariatric Surgery (BS) has emerged as a crucial therapeutic approach, demonstrating success in weight loss and comorbidity improvement. This study aimed to evaluate the outcomes of BS in a cohort of 48 Uruguayan patients and investigate the interplay between BS and clinical and metabolic features, with a specific focus on FSTL1, an emerging biomarker associated with obesity and inflammation. We quantitatively analyzed BS outcomes and constructed linear models to identify variables impacting BS success. The study revealed the effectiveness of BS in improving metabolic and clinical parameters. Importantly, variables correlating with BS success were identified, with higher pre-surgical FSTL1 levels associated with an increased effect of BS on BMI reduction. FSTL1 levels were measured from patient plasma using an ELISA kit pre-surgery and six months after. This research, despite limitations of a small sample size and limited follow-up time, contributes valuable insights into understanding and predicting the success of BS, highlighting the potential role of FSTL1 as a useful biomarker in obesity.

Prognostic Significance of Proteomics-Discovered Circulating Inflammatory Biomarkers in Patients With Pulmonary Arterial Hypertension.

BACKGROUND: Pulmonary arterial hypertension (PAH) ultimately leads to right ventricular failure and premature death. The identification of circulating biomarkers with prognostic utility is considered a priority. As chronic inflammation is recognized as key pathogenic driver, we sought to identify inflammation-related circulating proteins that add incremental value to current risk stratification models for long-term survival in patients with PAH. METHODS AND RESULTS: Plasma levels of 384 inflammatory proteins were measured with the proximity extension assay technology in patients with PAH (n=60) and controls with normal hemodynamics (n=28). Among these, 51 analytes were significantly overexpressed in the plasma of patients with PAH compared with controls. Cox proportional hazard analyses and C-statistics were performed to assess the prognostic value and the incremental prognostic value of differentially expressed proteins. A panel of 6 proteins (CRIM1 [cysteine rich transmembrane bone morphogenetic protein regulator 1], HGF [hepatocyte growth factor], FSTL3 [follistatin-like 3], PLAUR [plasminogen activator, urokinase receptor], CLSTN2 [calsyntenin 2], SPON1 [spondin 1]) were independently associated with death/lung transplantation at the time of PAH diagnosis after adjustment for the 2015 European Society of Cardiology/European Respiratory Society guidelines, the REVEAL (Registry to Evaluate Early and Long-Term PAH Disease Management) 2.0 risk scores, and the refined 4-strata risk assessment. CRIM1, PLAUR, FSTL3, and SPON1 showed incremental prognostic value on top of the predictive models. As determined by Western blot, FSTL3 and SPON1 were significantly upregulated in the right ventricle of patients with PAH and animal models (monocrotaline-injected and pulmonary artery banding-subjected rats). CONCLUSIONS: In addition to revealing new actors likely involved in cardiopulmonary remodeling in PAH, our screening identified promising circulating biomarkers to improve risk prediction in PAH, which should be externally confirmed.

The RNA landscape of the human placenta in health and disease.

The placenta is the interface between mother and fetus and inadequate function contributes to short and long-term ill-health. The placenta is absent from most large-scale RNA-Seq datasets. We therefore analyze long and small RNAs (~101 and 20 million reads per sample respectively) from 302 human placentas, including 94 cases of preeclampsia (PE) and 56 cases of fetal growth restriction (FGR). The placental transcriptome has the seventh lowest complexity of 50 human tissues: 271 genes account for 50% of all reads. We identify multiple circular RNAs and validate 6 of these by Sanger sequencing across the back-splice junction. Using large-scale mass spectrometry datasets, we find strong evidence of peptides produced by translation of two circular RNAs. We also identify novel piRNAs which are clustered on Chr1 and Chr14. PE and FGR are associated with multiple and overlapping differences in mRNA, lincRNA and circRNA but fewer consistent differences in small RNAs. Of the three protein coding genes differentially expressed in both PE and FGR, one encodes a secreted protein FSTL3 (follistatin-like 3). Elevated serum levels of FSTL3 in pregnant women are predictive of subsequent PE and FGR. To aid visualization of our placenta transcriptome data, we develop a web application ( https://www.obgyn.cam.ac.uk/placentome/ ).

FSTL1 aggravates cigarette smoke-induced airway inflammation and airway remodeling by regulating autophagy.

BACKGROUND: Cigarette smoke (CS) is a major risk factor for Chronic Obstructive Pulmonary Disease (COPD). Follistatin-like protein 1 (FSTL1), a critical factor during embryogenesis particularly in respiratory lung development, is a novel mediator related to inflammation and tissue remodeling. We tried to investigate the role of FSTL1 in CS-induced autophagy dysregulation, airway inflammation and remodeling. METHODS: Serum and lung specimens were obtained from COPD patients and controls. Adult female wild-type (WT) mice, FSTL1± mice and FSTL1flox/+ mice were exposed to room air or chronic CS. Additionally, 3-methyladenine (3-MA), an inhibitor of autophagy, was applied in CS-exposed WT mice. The lung tissues and serum from patients and murine models were tested for FSTL1 and autophagy-associated protein expression by ELISA, western blotting and immunohistochemical. Autophagosome were observed using electron microscope technology. LTB4, IL-8 and TNF-α in bronchoalveolar lavage fluid of mice were examined using ELISA. Airway remodeling and lung function were also assessed. RESULTS: Both FSTL1 and autophagy biomarkers increased in COPD patients and CS-exposed WT mice. Autophagy activation was upregulated in CS-exposed mice accompanied by airway remodeling and airway inflammation. FSTL1± mice showed a lower level of CS-induced autophagy compared with the control mice. FSTL1± mice can also resist CS-induced inflammatory response, airway remodeling and impaired lung function. CS-exposed WT mice with 3-MA pretreatment have a similar manifestation with CS-exposed FSTL1± mice. CONCLUSIONS: FSTL1 promotes CS-induced COPD by modulating autophagy, therefore targeting FSTL1 and autophagy may shed light on treating cigarette smoke-induced COPD.

Myokines in treatment-naïve patients with cancer-associated cachexia.

Cancer-associated cachexia is a complex metabolic syndrome characterized by weight loss and systemic inflammation. Muscle loss and fatty infiltration into muscle are associated with poor prognosis in cancer patients. Skeletal muscle secretes myokines, factors with autocrine, paracrine and/or endocrine action, which may be modified by or play a role in cachexia. This study examined myokine content in the plasma, skeletal muscle and tumor homogenates from treatment-naïve patients with gastric or colorectal stages I-IV cancer with cachexia (CC, N = 62), or not (weight stable cancer, WSC, N = 32). Myostatin, interleukin (IL) 15, follistatin-like protein 1 (FSTL-1), fatty acid binding protein 3 (FABP3), irisin and brain-derived neurotrophic factor (BDNF) protein content in samples was measured with Multiplex technology; body composition and muscle lipid infiltration were evaluated in computed tomography, and quantification of triacylglycerol (TAG) in the skeletal muscle. Cachectic patients presented lower muscle FSTL-1 expression (p = 0.047), higher FABP3 plasma content (p = 0.0301) and higher tumor tissue expression of FABP3 (p = 0.0182), IL-15 (p = 0.007) and irisin (p = 0.0110), compared to WSC. Neither muscle TAG content, nor muscle attenuation were different between weight stable and cachectic patients. Lumbar adipose tissue (AT) index, visceral AT index and subcutaneous AT index were lower in CC (p = 0.0149, p = 0.0455 and p = 0.0087, respectively), who also presented lower muscularity in the cohort (69.2% of patients; p = 0.0301), compared to WSC. The results indicate the myokine profile in skeletal muscle, plasma and tumor is impacted by cachexia. These findings show that myokines eventually affecting muscle wasting may not solely derive from the muscle itself (as the tumor also may contribute to the systemic scenario), and put forward new perspectives on cachexia treatment targeting myokines and associated receptors and pathways.

Clinical significance of FSTL 1, Bax, Bcl-2 in acute cerebral infarction and its relationship with hemorrhagic transformation.

OBJECTIVE: Acute cerebral infarction (ACI) is the most common type of acute cerebrovascular disease so far, and its incidence rate has been increasing in recent years. At present, the methods of diagnosing ACI in clinic are extremely complicated, and an effective index that can effectively diagnose ACI is urgently needed in clinic. This study is designed to investigate the clinical significance of Follistatin-like protein 1 (FSTL1), Bax and Bcl-2 in ACI. PATIENTS AND METHODS: A total of 84 cases of ACI patients admitted to our hospital from September 2017 to September 2019 and 90 cases of healthy subjects undergoing physical examination at the same time were selected as the research objects for prospective analysis. The concentrations of FSTL1, Bax and Bcl-2 in the peripheral blood of objects in the two groups were detected to analyze the diagnostic value of FSTL1, Bax and Bcl-2 for ACI, and the correlation of FSTL 1, Bax and Bcl-2 with the infarct size, treatment method and hemorrhagic transformation. Another 20 SD rats were purchased, among which 10 rats were randomly selected for ACI modeling. FSTL1 concentration, Bax and Bcl-2 protein expression in brain tissues of ACI rats and normal rats were detected. RESULTS: FSTL1 and Bax in peripheral blood of ACI patients were higher than those of healthy subjects (p<0.050), and Bcl-2 was lower than those of healthy subjects (p<0.050). It was detected that FSTL1, Bax and Bcl-2 had good diagnostic value for patients with ACI (p<0.001). FSTL1 and Bax decreased while Bcl-2 increased in patients treated with thrombolytic therapy (p<0.050). And FSTL1, Bax and Bcl-2 were closely related to infarct size and hemorrhagic transformation (p<0.050). Logistic regression analysis showed that NIHSS score, atrial fibrillation, infarct volume, FSTL1 and Bax were independent risk factors affecting hemorrhagic transformation in ACI patients (p<0.050), and Bcl-2 was an independent protective factor affecting hemorrhagic transformation in ACI patients (p<0.050). The concentration of FSTL1 and the expression of Bax protein in rat brain tissue were also higher than that in normal rats, while Bcl-2 was lower than that in normal rats (p < 0.001). CONCLUSIONS: FSTL1, Bax and Bcl-2 are involved in the occurrence and development of ACI and are closely related to the hemorrhagic transformation of patients. The mechanism by which FSTL1 promotes the occurrence of ACI might be related to promoting the occurrence of inflammatory responses in the brain tissue of patients or accelerating the apoptosis of neurons.

Haplodeletion of Follistatin-Like 1 Attenuates Radiation-Induced Pulmonary Fibrosis in Mice.

PURPOSE: Radiation-induced pulmonary fibrosis (RIPF) is a severe and life-threatening complication of radiation therapy in patients with thoracic cancer; however, the exact molecular mechanisms remain unknown, and there is no effective treatment method in clinic. Here, we assessed the role of follistatin-like 1 (Fstl1) in RIPF. METHODS AND MATERIALS: Protein and messenger RNA levels of Fstl1 in lung tissues from symptomatic RIPF patients, Rhesus macaques, and mice were assessed. Fibrotic and inflammatory responses to radiation-induced lung injury and accumulation of myofibroblasts in Fstl1 haplodeficient (Fstl1+/-) mice were determined. Finally, radiation-induced differentiation and activation of fibroblasts in primary Fstl1+/- lung fibroblasts were evaluated. RESULTS: FSTL1 amounts were significantly increased in serum and/or radiation-injured lung specimens from symptomatic RIPF patients, Rhesus macaques, and mice. Haplodeletion of Fstl1 in Fstl1+/- mice was protective against x-ray-induced lung injury in mice in vivo, as well as myofibroblast activation in vitro. CONCLUSIONS: These findings suggest that Fstl1 plays an important role in lung fibrosis and may offer a potential approach to attenuate RIPF in radiation therapy of patients with thoracic cancer.

Follistatins in glucose regulation in healthy and obese individuals.

AIMS: It has been suggested recently that follistatin (FST) and its homologous protein, follistatin-like 3 (FSTL3), may be a therapeutic target in the treatment of type 2 diabetes because of their glucose-regulatory effects in rodents. MATERIALS AND METHODS: We investigated this hypothesis in humans by studying the physiology of a possible glycaemia-follistatin feedback loop, that is, whether glucose, but not lipid intake (oral or intravenous), can regulate circulating FST and FSTL3 in healthy humans (n = 32), whether the levels of follistatins change in response to various types of bariatric operation in morbidly obese individuals, with or without type 2 diabetes (n = 41), and whether such changes are associated prospectively with improvement of glucose homeostasis/insulin sensitivity. RESULTS: In healthy individuals, circulating FST decreases after intravenous or oral glucose intake compared to controls, indicating the presence of a negative feedback mechanism. In morbid obesity, insulin resistance, glycaemia, circulating FST and FSTL3 are all reduced (by 22%-33%) after Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy. Importantly, the changes in circulating FST 3 months after bariatric surgery are associated prospectively with the changes in glucose, insulin, HOMA-IR and HbA1c observed 6 months postoperatively in individuals with and without type 2 diabetes. CONCLUSIONS: Our findings provide evidence of an important role of FST in glucose homeostasis in healthy individuals as well as in severely obese individuals with insulin resistance and type 2 diabetes. Our data extend recent results from animal studies to humans and support the need for further evaluation of FST inactivation strategies for targeting hyperglycaemia and insulin resistance.

Serum Levels of Activins, Follistatins, and Growth Factors in Neoplasms of the Breast: A Case-Control Study.

Context: Breast cancer is the most common malignancy in women. Noninvasive biomarkers are needed for its early diagnosis and/or prognosis. Objective: The aim of this case-control study was the comparison of serum activins, follistatins, and members of the IGF family levels in women with benign vs malignant breast neoplasms vs apparently healthy controls. Design and Patients: Women with breast benign (n = 100) or malignant tumors (n = 145) and disease-free controls (n = 100) were recruited. Women with breast cancer were subsequently subdivided into recently diagnosed/treatment-naive (n = 112) and chemotherapy-treated (n = 33). Anthropometric, demographic, biochemical, and histological data were recorded. Setting: A breast cancer clinic in Thessaloniki, Greece. Main Outcome Measures: Serum levels of activin A, activin B, follistatin, follistatin-like (FSTL)-3, total IGF-1, total and intact insulin-like growth factor binding protein (IGFBP)-4 and pregnancy-associated plasma protein-A (PAPP-A) were measured with highly specific ELISA kits. Results: In adjusted comparisons, substantial differences in FSTL-3, total and intact IGFBP-4, PAPP-A, and total IGF-1 were observed between groups. In logistic regression analysis, primarily total IGFBP-4 levels were independently associated with the overall presence of breast malignancy. FSTL-3 was the only variable that could distinguish between a benign vs malignant breast mass. In linear regression analysis, FSTL-3 was independently associated with tumor size. Conclusions: We showed that members of the IGF-1/IGFBP-4/PAPP-A axis and FSTL-3 may serve as surrogate markers in breast cancer. Future mechanistic and longitudinal studies and/or clinical trials are needed to explore the efficacy of these molecules as noninvasive biomarkers and their possible therapeutic potential in breast cancer.

Hepatic expression profiling identifies steatosis-independent and steatosis-driven advanced fibrosis genes.

Chronic liver disease (CLD) is associated with tissue-destructive fibrosis. Considering that common mechanisms drive fibrosis across etiologies, and that steatosis is an important cofactor for pathology, we performed RNA sequencing on liver biopsies of patients with different fibrosis stages, resulting from infection with hepatitis C virus (HCV) (with or without steatosis) or fatty liver disease. In combination with enhanced liver fibrosis score correlation analysis, we reveal a common set of genes associated with advanced fibrosis, as exemplified by those encoding the transcription factor ETS-homologous factor (EHF) and the extracellular matrix protein versican (VCAN). We identified 17 fibrosis-associated genes as candidate EHF targets and demonstrated that EHF regulates multiple fibrosis-associated genes, including VCAN, in hepatic stellate cells. Serum VCAN levels were also elevated in advanced fibrosis patients. Comparing biopsies from patients with HCV with or without steatosis, we identified a steatosis-enriched gene set associated with advanced fibrosis, validating follistatin-like protein 1 (FSTL1) as an exemplar of this profile. In patients with advanced fibrosis, serum FSTL1 levels were elevated in those with steatosis (versus those without). Liver Fstl1 mRNA levels were also elevated in murine CLD models. We thus reveal a common gene signature for CLD-associated liver fibrosis and potential biomarkers and/or targets for steatosis-associated liver fibrosis.

Follistatin-Like Protein-1 Upregulates Dendritic Cell-Based Immunity in Patients with Nasopharyngeal Carcinoma.

Follistatin-like protein-1 (FSTL1) is an inflammatory factor that can induce an inflammatory response and is expressed in cancers. However, little is known about its content and function in nasopharyngeal carcinoma (NPC). Interleukin (IL)-12 and IL-4 are primarily secreted by dendritic cells (DCs) and activated T lymphocytes, respectively; these factors can induce Th cell differentiation and cytotoxic lymphocyte production, both of which facilitate tumors through the STAT4 and STAT6 pathways, respectively. In this study, the relationship between FSTL1 and both IL-12 and IL-4 as well as the functional mechanism of these cytokines was explored. Enzyme-linked immunosorbent assay, flow cytometry, and Western blotting were used to assess the levels of key inflammatory factors and DC markers as well as elucidate the mechanism by which FSTL-1 mediates and exerts it antitumor effects. The results revealed that serum FSTL1 and IL-12 levels were significantly decreased in NPC patients compared with those in the control group (P < 0.05); conversely, IL-4 levels were increased (P < 0.05). Supernatants from the experimental groups (EGs) contained higher IL-4 and IL-12 levels than those from the control groups (P < 0.05). Additionally, phosphorylated-STAT6 and phosphorylated-STAT4 were increased in the EGs (P < 0.05). These results suggest that DC-mediated immunity was activated by FSTL1, which leads to an increase of IL-12 and IL-4 production and consequently activates the STAT4 and STAT6 pathways through upregulation of STAT4 and STAT6 phosphorylation, respectively.

The Correlation between FSTL1 Expression and Airway Remodeling in Asthmatics.

BACKGROUND: Asthma is characterized by airway remodeling. Follistatin-like protein 1 (FSTL1) is an extracellular glycoprotein. Recent studies suggest that FSTL1 may participate in the pathogenesis of asthma. OBJECTIVES: To analyze the association between FSTL1 and some parameters and inspect the role of FSTL1 in asthma. METHODS: We examined FSTL1 levels in 32 asthmatics and 25 controls. All subjects enrolled had routine blood tests, spirometry, and impulse oscillometry performed. Additionally, 15 of the 32 asthmatics underwent fibre optic bronchoscopy. Spearman rank analysis was performed to detect the correlation between FSTL1 and other parameters. RESULTS: Plasma FSTL1 levels were higher in asthmatics (130.762 ± 46.029 ng/mL) than in controls (95.408 ± 33.938 ng/mL) (p = 0.009). Plasma FSTL1 levels were associated with fibrosis levels around the airways (rs = 0.529, p = 0.043) and α-smooth muscle actin (α-SMA) (rs = 0.554, p = 0.032). FSTL1 levels in bronchoalveolar lavage fluid were associated with collagen I (rs = 0.536, p = 0.040), α-SMA (rs = 0.561, p = 0.029), fibrosis levels (rs = 0.779, p = 0.001), and the thickness of the airway reticular basement membrane (RBM) (rs = 0.660, p = 0.007). CONCLUSIONS: FSTL1 levels in asthmatics were linked with increased smooth muscle mass and thickened RBM. FSTL1 may contribute to airway remodeling in asthmatics.

Follistatin-like protein 1 promotes inflammatory reactions in nucleus pulposus cells by interacting with the MAPK and NFκB signaling pathways.

OBJECTIVE: Follistatin-like protein 1 (FSTL1) is a well-known mediator of inflammation. Intervertebral disc disease is an inflammatory disorder. Here, we investigated the role of FSTL1 in the intervertebral discs inflammation. METHODS: Expression of FSTL1 in nucleus pulposus tissues from rats and human was determined by immunohistochemistry staining and western blot analysis. The expression levels of tumor necrosis factor-α (TNF-α), interleukin1-ß (IL-1ß) and matrix metalloproteinase 13 (MMP-13) in human and rat nucleus pulposus tissues were measured by immunohistochemistry staining. The mitogen-activated protein kinase (MAPK) and nuclear factor-kappa B (NFκB) signaling pathways were detected by western blotting. RESULTS: FSTL1 serum levels were significantly increased in lumbar disc herniation patients and had a positive correlation with Visual Analogue Scores. Additionally, FSTL1 expression was significantly increased in extrusion group compared with protrusion and control groups. Furthermore, FSTL1 expression was significantly increased in intervertebral disc degeneration models of rats. Immunohistochemistry staining demonstrated that the levels of TNF-α, IL-1ß and MMP-13 were increased in the pathogenesis of intervertebral disc disease. Recombinant human FSTL1 significantly increased the production of proinflammatory cytokines in vitro. In addition, FSTL1 promoted inflammation by activating c-Jun N-terminal kinase (JNK), extracellular regulated protein kinases 1/2(ERK1/2) and NFκB signaling. CONCLUSIONS: These data imply that FSTL1 expression was increased in the pathogenesis of intervertebral disc disease. Importantly, FSTL1 promoted inflammatory catabolism in the nucleus pulposus by activating JNK, ERK 1/2/MAPK and NFκB signaling.

Growth differentiation factor-15 (GDF-15) levels are associated with cardiac and renal injury in patients undergoing coronary artery bypass grafting with cardiopulmonary bypass.

OBJECTIVE: Growth differentiation factor-15 (GDF-15) has been identified as a strong marker of cardiovascular disease; however, no data are available concerning the role of GDF-15 in the occurrence of organ dysfunction during coronary artery bypass grafting (CABG) associated with cardiopulmonary bypass (CPB). METHODS: Five arterial blood samples were taken sequentially in 34 patients from anesthesia induction (IND) until 24 h after arrival at the intensive care unit (ICU). Plasma levels of GDF-15, follistatin-like 1 (FLST1), myeloperoxidases (MPO), hydroperoxides and plasma antioxidant status (PAS) were measured at each time-point. Markers of cardiac (cardiac-troponin I, cTnI) and renal dysfunction (neutrophil gelatinase-associated lipocalin, NGAL) and other classical biological factors and clinical data were measured. RESULTS: Plasma GDF-15 levels increased gradually during and after surgery, reaching nearly three times the IND levels in the ICU (3,075±284 ng/L vs. 1,061±90 ng/L, p<0.001). Plasma MPO levels increased dramatically during surgery, attaining their highest level after unclamping (UNCLAMP) (49±11 ng/mL vs. 1,679±153 ng/mL, p<0.001) while PAS significantly decreased between IND and UNCLAMP (p<0.05), confirming the high oxidative status induced by this surgical procedure. ICU levels of GDF-15 correlated positively with cTnI and NGAL (p = 0.006 and p = 0.036, respectively), and also with hemoglobin and estimated glomerular filtration rate (eGFR). Among all the post-operative biomarkers available, only eGFR, NGAL and GDF-15 measured at ICU arrival were significantly associated with the onset of acute kidney injury (AKI). Patients with a EuroSCORE >3 were shown to have higher GDF-15 levels. CONCLUSIONS: During cardiac surgery associated with CPB, GDF-15 levels increased substantially and were associated with markers of cardiac injury and renal dysfunction.

Obesity and low-grade inflammation increase plasma follistatin-like 3 in humans.

BACKGROUND: Rodent models suggest that follistatin-like 3 (fstl3) is associated with diabetes and obesity. In humans, plasma fstl3 is reduced with gestational diabetes. In vitro, TNF-α induces fstl3 secretion, which suggests a link to inflammation. OBJECTIVE: To elucidate the association between plasma fstl3 and obesity, insulin resistance, and low-grade inflammation in humans. STUDY DESIGN: Plasma fstl3 levels were determined in a cross-sectional study including three groups: patients with type 2 diabetes, impaired glucose tolerance, and healthy controls. In addition, lipopolysaccharide (LPS), TNF-α, or interleukin-6 (IL-6) as well as a hyperinsulinemic euglycemic clamp were used to examine if plasma fstl3 was acutely regulated in humans. RESULTS: Plasma fstl3 was increased in obese subjects independent of glycemic state. Moreover, plasma fstl3 was positively correlated with fat mass, plasma leptin, fasting insulin, and HOMA B and negatively with HOMA S. Furthermore plasma fstl3 correlated positively with plasma TNF-α and IL-6 levels. Infusion of LPS and TNF-α, but not IL-6 and insulin, increased plasma fstl3 in humans. CONCLUSION: Plasma fstl3 is increased in obese subjects and associated with fat mass and low-grade inflammation. Furthermore, TNF-α increased plasma fstl3, suggesting that TNF-α is one of the inflammatory drivers of increased systemic levels of fstl3.

[Expression of serum FSTL-1 in bone metastasis of prostate cancer and its clinical implication].

OBJECTIVE: To investigate the expression of follistatin-like protein 1 (FSTL-1) in bone metastasis of prostate cancer (BMPC), the correlation of serum FSTL-1 with the chronic inflammatory factor interleukin-6 (IL-6) and bone morphogenetic protein 6 (BMP6) , and the clinical application value of serum FSTL-1 in BMPC. METHODS: Using ELISA, we measured the expression levels of serum FSTL-1, IL-6, and BMP6 in 35 patients with BMPC and another 30 with benign prostatic hyperplasia (BPH) and performed correlation analysis on the data obtained. RESULTS: Compared with the BPH controls, the BMPC patients showed a significantly decreased expression of serum FSTL-1 ([34.45 ± 12.35] µg/L vs [20.23 ± 8.69] µg/L, P < 0.01) and increased levels of IL-6 ([11.21 ± 8.62] µg/L vs [23.56 ± 20.12] µg/L, P < 0.05) and BMP6 ([293.50 ± 39.72] µg/L vs [428.30 ± 178.40] µg/L, P < 0.05). There was a significant negative correlation between the level of serum FSTL-1 and those of IL-6 and BMP6 in the BMPC patients, with correlation coefficients of -0.971 and -0.972, respectively (P < 0.05). CONCLUSION: The expression of serum FSTL-1 decreases in patients with bone metastasis of prostate cancer, and it is correlated with the levels of inflammatory factor and cell transformation factor. This finding offers a novel biological marker for the development and progression of prostate cancer as well as a new biological target factor for its intervention.

Regulation of follistatin-like protein 1 expression and secretion in primary human skeletal muscle cells.

Follistatin-like protein 1 (Fstl1) is a secreted glycoprotein of the follistatin family. Fstl1 is secreted by C2C12 cells, and Akt1 over-expression in skeletal muscle leads to its induction in muscle and increased circulating levels. So far, secretion of Fstl1 by human myotubes and the effect of exercise on its circulating levels have not been investigated. Here, we examined both the regulation of Fstl1 expression and secretion in primary human skeletal muscle cells and the effect of acute exercise on Fstl1 serum concentrations in humans. We show that human myotubes express and secrete Fstl1 in a differentiation-dependent manner. Furthermore, IFNγ and IL-1ß significantly increase Fstl1 secretion. Electrical pulse stimulation (EPS)-induced contractile activity of myotubes did not regulate Fstl1. Interestingly, we observed that 60 min cycling increased serum Fstl1 level by 22%. In conclusion, we demonstrate that Fstl1 is expressed and secreted by human myotubes and plasma Fstl1 levels are increased after exercise.

Serum S100A8/A9, but not follistatin-like protein 1 and interleukin 18, may be a useful biomarker of disease activity in adult-onset Still's disease.

OBJECTIVE: S100A8/A9, follistatin-like protein 1, and interleukin 18 (IL-18) have been suggested as biomarkers of disease activity in patients with systemic juvenile idiopathic arthritis or adult-onset Still's disease (AOSD). We investigated the clinical significance of these factors in AOSD. METHODS: Blood samples were collected from 36 patients with AOSD, 40 patients with rheumatoid arthritis (RA), and 33 healthy controls. Of the patients with AOSD, followup samples were collected from 16 patients after resolution of disease activity. RESULTS: Serum levels of S100A8/A9 (11.77 ± 8.84 µg/ml) in AOSD patients were higher than those in RA patients (3.53 ± 3.43 µg/ml; p < 0.001) and controls (2.49 ± 1.83 µg/ml; p < 0.001). Follistatin-like protein 1 levels in AOSD were not different from those in RA and controls. IL-18 levels in AOSD (7560.3 ± 7577.6 pg/ml) were higher than those in RA (217.7 ± 292.1 pg/ml; p < 0.001) and controls (139.2 ± 86.2 pg/ml; p < 0.001). The sensitivity and specificity of IL-18 for diagnosing AOSD was highest with a cutoff value of 366.1 pg/ml. Serum S100A8/A9 correlated with leukocyte count, erythrocyte sedimentation rate, C-reactive protein, ferritin, and systemic disease score; however, IL-18 correlated only with ferritin and systemic disease score. S100A8/A9 was decreased after disease activity was resolved in followup of AOSD patients (9.96 ± 7.35 µg/ml in active AOSD vs 3.6 ± 4.77 µg/ml in resolved cases; p = 0.001). The change of S100A8/A9 was well correlated with that of systemic disease score. CONCLUSION: The data suggest that serum S100A8/A9 may be a useful biomarker for evaluating disease activity in patients with AOSD.

Serum concentrations of myostatin and myostatin-interacting proteins do not differ between young and sarcopenic elderly men.

Sarcopenia is the loss of muscle size and function during ageing. The aim of this study was to test whether serum concentrations of myostatin and interacting proteins (GASP-1, FLRG, and follistatin) differed between young and elderly sarcopenic men. Isometric knee extensor maximal voluntary contraction and quadriceps cross-sectional area (magnetic resonance imaging measurement) were significantly higher in young (22 ± 2 years; 266 ± 54 N/m; 8,686 ± 1,154 mm(2)) than in mildly sarcopenic (69 ± 3 years; 183 ± 17 N/m; 6,621±718 mm(2)) and severely sarcopenic men (76 ± 6 years; 127 ± 23 N/m; 5,846 ± 591 mm(2)), respectively (p ≤ .01 for all comparisons). There was a trend (p = .06) toward higher FLRG in young (20 ± 8 ng/mL) than in mildly (15 ± 6 ng/mL) and severely sarcopenic men (17 ± 8 ng/mL). Myostatin, follistatin, GASP-1, tumor necrosis factor α, and interleukin-6 did not differ significantly. Insulin-like growth factor-1 and free testosterone were both significantly lower in sarcopenic men (p < .001). This suggests that altered serum concentrations of myostatin and myostatin-interacting proteins are not contributing to sarcopenia with the possible exception of FLRG.

Prediction of gestational diabetes mellitus by maternal factors and biomarkers at 11 to 13 weeks.

OBJECTIVE: To develop a model for the prediction of gestational diabetes mellitus (GDM) from maternal characteristics and biochemical markers at 11 to 13 weeks' gestation. METHODS: A prospective screening study on early prediction of pregnancy complications (n = 11, 464), including 297 (2.6%) cases of GDM was used to create the predictive model of GDM based on maternal characteristics. Maternal serum concentrations of adiponectin, follistatin-like-3 (FSTL3) and sex hormone-binding globulin (SHBG) were measured in a case-control study of 80 women who developed GDM and 300 controls. RESULTS: In the screening study, maternal age, body mass index, racial origin, previous history of GDM and macrosomic neonate were significant independent predictors of future GDM. In the GDM group, compared to controls, the median multiple of the normal median adiponectin (0.66; IQR: 0.5-0.9 vs 1.02; IQR: 0.7-1.29) and SHBG (0.81; IQR: 0.6-1.04 vs 1.02; IQR: 0.8-1.2) was lower (p < 0.05), but FSTL3 was not significantly different. In screening for GDM by maternal characteristics, the detection rate was 61.6% at a false-positive rate of 20% and the detection increased to 74.1% by the addition of adiponectin and SHBG. CONCLUSION: First-trimester screening for GDM can be provided by a combination of maternal characteristics and biomarkers.