Follistatin-like 1 (FSTL1) levels as potential early biomarker of cardiovascular disease in a Mexican population.

Cardiovascular diseases (CVD) are the leading cause of death globally. In recent years, follistatin-like protein 1 (FSTL1) has been proposed as an emerging potential clinical biomarker of CVD, since its concentration is upregulated in heart failure. The aim of the present study was to evaluate the association of FSTL1 levels and classic biomarkers with the risk of CVD in Mexican population. A case-control study was carried out in patients with cardiovascular diseases (CVD), arterial hypertension, but not CVD (cardiovascular risk factor-CRF), and healthy controls (control group) from the Mexican Institute of Social Security. Lipid profile, homocysteine (Hcys), serum amyloid A (SAA), FSTL1 concentration, PON1 concentration and activities [Arylesterase (ARE), and Lactonase (LAC)] were evaluated. High levels of FSTL1 were found in the CRF group and a positive association of FSTL1 (OR = 4.55; 95% CI 1.29-16.04, p = 0.02) with the presence of arterial hypertension, as well as Hcys (OR, 3.09; 95% CI 1.23-7.76, p = 0.02) and SAA (OR, 1.03; 95% CI 1.01-1.05, p < 0.01) with the presence of CVD. LAC activity (OR, 0.26; 95% CI 0.07-0.94, p = 0.04) and PON1 concentration (OR, 0.17; 95% CI 0.05-0.62, p = 0.01) were associated with a decrease in OR belonging to the group with CVD. Our results suggest that FSTL1 may be a useful biomarker for monitoring cardiovascular risk in clinical settings. However, longitudinal studies are needed to evaluate how FSTL1 could influence the association of PON1 activity and Hcys with CVD.

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.

Association between Plasma Follistatin-like Protein 1 Levels and the Presence and Severity of Coronary Artery Disease.

Follistatin-like protein 1 (FSTL1) is a secreted glycoprotein known for its role in inflammation. However, plasma FSTL1 levels in patients with coronary artery disease (CAD) have not been fully elucidated. Thus, in this study, we investigated the plasma FSTL1 levels of 350 patients who underwent elective coronary angiography. The severity of CAD was represented as the numbers of > 50% stenotic vessels and segments and the severity score. CAD was detected in 196 patients, of whom 84 had 1-vessel disease (1-VD), 62 had 2-VD, and 50 had 3-VD. Plasma high-sensitivity C-reactive protein (hsCRP) levels were higher in patients with CAD than in those without CAD (median 0.56 versus 0.44 mg/L, P < 0.01). Notably, plasma FSTL1 levels were higher in patients with CAD than in those without CAD (median 4.05 versus 3.47 ng/mL, P < 0.02). A stepwise increase in FSTL1 levels was found depending on the number of > 50% stenotic vessels: 3.47 in CAD (-), 3.74 in 1-VD, 4.42 in 2-VD, and 4.65 ng/mL in 3-VD (P < 0.05). FSTL1 levels also correlated with the number of > 50% stenotic segments and the severity score (r = 0.14 and r = 0.15, respectively, P < 0.005) and hsCRP levels (r = 0.10, P < 0.05). In the multivariate analysis, FSTL1 levels were an independent factor associated with CAD. The odds ratio for CAD was 1.61 (95% CI = 1.01-2.58) for high FSTL1 level of > 3.6 ng/mL (P < 0.05). In conclusion, plasma FSTL1 levels in patients with CAD were found to be high and associated with the presence and severity of CAD, thus, suggesting that FSTL1 may play a role in the progression of coronary atherosclerosis.

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.

High circulating follistatin-like protein 1 as a biomarker of a metabolically unhealthy state.

The inflammatory biomarkers that fully characterize the metabolically unhealthy (MU) state-which is a risk factor for cardiovascular disease (CVD)-remain unclear. Recent studies suggest follistatin-like protein 1 (FSTL1) could be used as a biomarker for inflammation and CVD, however there is little information on FSTL1 levels in the MU state. We aimed to evaluate the associations between FSTL1, the presence of MU state and subclinical coronary atherosclerosis. In a cross-sectional study, we evaluated FSTL1 levels and their relationship with the presence of MU state and coronary artery plaques in 230 Korean patients. Significant increase in FSTL1 levels was observed in subjects with MU state (p = 0.020), but not those with obesity state according to body mass index criteria (p = 0.790). After adjusting for confounders, the odd ratio (OR) for the MU state among patients in the highest FSTL1 tertile (T3) was higher in comparison with the lowest tertile (T1) (OR = 3.60, 95% confidence interval [95% CI] = 1.20-10.83). In a subgroup (n = 66), FSTL1 levels were also marginally higher in patients with plaques (p = 0.098). The OR for plaque presence in patients with T3 was significantly higher in comparison with T1 after adjusting for confounders (OR = 12.51, 95% CI = 1.15-135.73). Plasma FSTL1 may be a useful biomarker for the risk of MU state and CVD.

Autophagy plays a role in FSTL1-induced epithelial mesenchymal transition and airway remodeling in asthma.

Asthma is a chronic disease related to airway hyperresponsiveness and airway remodeling. Airway remodeling is the important reason of refractory asthma and is associated with differentiation of airway epithelia into myofibroblasts via epithelial-mesenchymal transition (EMT) to increase the process of subepithelial fibrosis. There is growing evidence that autophagy modulates remodeling. However, the underlying molecular mechanisms of these effects are still unclear. In this study, we hypothesized that Follistatin-like 1 (FSTL1) promotes EMT and airway remodeling by intensifying autophagy. With the use of transmission electron microscopy (TEM), double-membrane autophagosomes were detected in the airways of patients and mice. More autophagosomes were in patients with asthma and OVA-challenged mice compared with healthy controls. The expression of FSTL1 and beclin-1 was upregulated in the airways of patients with asthma and OVA-challenged mice, accompanied by airway EMT and remodeling. In OVA-challenged Fstl1+/- mice, the degree of airway remodeling and autophagy was decreased compared with control mice. The effects of FSTL1 on autophagy and EMT were also tested in 16HBE cells in vitro. Additionally, inhibition of autophagy by using LY-294002 and siRNA-ATG5 reduced the FSTL1-induced EMT in 16HBE cells, as measured by E-cadherin, N-cadherin, and vimentin expression. In line herewith, administration of LY-294002 reduced the expression of autophagy, EMT, and airway remodeling markers in FSTL1-challenged WT mice. Taken together, our study suggests that FSTL1 may induce EMT and airway remodeling by activating autophagy. These findings may provide novel avenues for therapeutic research targeting the autophagy and FSTL1 pathway, which may be beneficial to patients with refractory asthma.

FSTL3 is increased in renal dysfunction.

BACKGROUND: Follistatin-like 3 (FSTL3) is a novel cytokine that regulates insulin sensitivity and counteracts activin/myostatin signalling. In the present study, regulation of FSTL3 in renal dysfunction was investigated in both human chronic kidney disease (CKD) and acute kidney dysfunction (AKD). Furthermore, mFSTL3 expression was analysed in insulin-sensitive tissues in a mouse model of CKD. METHODS: Circulating FSTL3 was quantified by enzyme-linked immunosorbent assay in 581 patients with CKD covering the whole spectrum of estimated glomerular filtration rate (eGFR) categories from G1 to G5. Furthermore, FSTL3 was measured in 61 patients before and within 30 h after elective unilateral nephrectomy, an established model of AKD. Moreover, mFSTL3 mRNA expression was investigated in an animal CKD model, that is, eNOS-/-db/db mice, and compared with littermate controls. RESULTS: Median circulating FSTL3 levels significantly and continuously increased with deteriorating renal function (eGFR category G1: 6.1; G2: 8.2; G3: 12.7; G4: 18.5; G5: 32.1 µg/L; P < 0.001). In both human CKD and AKD, renal dysfunction remained the strongest independent predictor of FSTL3 serum concentrations in multivariate analyses. FSTL3 was independently associated with an adverse cardiometabolic profile. In CKD mice, hepatic mFSTL3 mRNA expression was increased more than 6-fold as compared with controls. CONCLUSIONS: Circulating FSTL3 is significantly and independently associated with renal function in both patients with CKD and AKD. Hepatic mFSTL3 mRNA upregulation might contribute to increased FSTL3 levels in CKD. Our results are in agreement with the hypothesis that FSTL3 is eliminated by the kidneys and might counteract adverse activin/myostatin signalling observed in renal dysfunction.

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.

[Novelties in the treatment of heart failure]. / Novinky v lécbe srdecního selhání.

Heart failure (HF) is a complex clinical syndrome which is manifested by characteristic symptoms and objective signs of cardiac insufficiency. The incidence of HF, particularly its chronic form, is estimated 0.4-2 % in the central and western Europe, with an increase in higher age groups, affecting 10-20 % of the population aged over 80. With respect to its growing incidence and prevalence, novel modalities of pharmacological and non-pharmacological treatment are being developed in order to improve quality of life and survival of the affected patients. This review based on up-to-date guidelines focuses in the first part on brief description of the possibilities of diagnosing heart failure, including the novelties arising out from the latest clinical and preclinical studies (such as soluble ST2, FSTL1, etc), further it concentrates on innovations in pharmacological treatment of chronic (ivabradine, ARNI, gliflozins) and acute (ularitide, serelaxin, nesiritide) HF. The last part provides an overview of available non-pharmacological HF therapeutics options (modulation of cardiac contraction, influencing the activity of sympathetic and parasympathetic nervous systems and permanent and temporary device support).Key words: ARNI - ECMO - gliflozins - heart failure - modulation of sympathetic and parasympathetic nervous systems - sacubitril-valsartan - therapy.

[Change in serum follistatin-like protein 1 and its clinical significance in children with chronic heart failure].

OBJECTIVE: To 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. METHODS: A 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. RESULTS: Before 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). CONCLUSIONS: FSTL1 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.

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.

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.

Plasma follistatin-like protein 1 is elevated in Kawasaki disease and may predict coronary artery aneurysm formation.

OBJECTIVE: To determine whether plasma levels of follistatin-like protein 1 (FSTL-1), a pro-inflammatory protein produced by mesenchymal tissue, including cardiac myocytes, correlate with the development of Kawasaki disease (KD) and coronary artery aneurysms (CAA). STUDY DESIGN: FSTL-1 plasma levels were measured serially with enzyme-linked immunosorbent assay in 48 patients with KD at time of diagnosis and, when available, 2 weeks, 6 weeks, and 6 months after onset of disease. These were compared with FSTL-1 plasma levels in 23 control subjects. Data were analyzed with generalized estimating equations. RESULTS: Plasma FSTL-1 levels were elevated in patients with acute KD compared with control subjects (P = .0086). FSTL-1 levels remained significantly elevated at 2 weeks after disease onset, but returned to control levels by 6 months. Seven patients with CAA had significantly higher FSTL-1 levels at the time of diagnosis than patients in whom aneurysms did not develop (P = .0018). Sensitivity and specificity rates for CAA at a specific FSTL-1 cutoff point (178 ng/mL) were 85% and 71%. CONCLUSIONS: Plasma levels of FSTL-1 are elevated in acute KD and may predict cardiac morbidity in this disease. These results suggest a possible role for FSTL-1 in the formation of CAAs.

Alterations of maternal serum and placental follistatin-like 3 and myostatin in pre-eclampsia.

AIM: To clarify the alterations of myostatin, a member of the transforming growth factor-ß superfamily, and follistatin-like 3 (FSTL3), a binding protein for myostatin, in pre-eclamptic women. METHODS: Samples of blood and placenta were collected from 40 pre-eclamptic women and 40 controls. The serum level and placental expression of FSTL3 and myostatin were determined with enzyme-linked immunosorbent assay, real-time polymerized chain reaction and western blotting. RESULTS: The serum levels of myostatin and FSTL3 were significantly higher in pre-eclamptic women than in the controls (P < 0.001 for both). Placental expression of myostatin and FSTL3 were also significantly increased in the pre-eclamptic placenta compared with that of the controls (P < 0.001 for both); however, there were no significant differences in myostatin or FSTL3 in either the maternal serum or the placenta in women with mild or severe pre-eclampsia (P > 0.05 for both). CONCLUSION: The serum levels and placental expression of myostatin and FSTL3 are elevated in pre-eclampsia, suggesting the role of myostatin and its binding protein in pre-eclampsia.

The Activin/FLRG Pathway Associates with Poor COVID-19 Outcomes in Hospitalized Patients.

A subset of hospitalized COVID-19 patients, particularly the aged and those with comorbidities, develop the most severe form of the disease, characterized by acute respiratory disease syndrome (ARDS), coincident with experiencing a "cytokine storm." Here, we demonstrate that cytokines which activate the NF-κB pathway can induce activin A. Patients with elevated activin A, activin B, and FLRG at hospital admission were associated with the most severe outcomes of COVID-19, including the requirement for mechanical ventilation, and all-cause mortality. A prior study showed that activin A could decrease viral load, which indicated there might be a risk to giving COVID-19 patients an inhibitor of activin. To evaluate this, the role for activin A was examined in a hamster model of SARS-CoV-2 infection, via blockade of activin A signaling. The hamster model demonstrated that use of an anti-activin A antibody did not worsen the disease and there was no evidence for increase in lung viral load and pathology. The study indicates blockade of activin signaling may be beneficial in treating COVID-19 patients experiencing ARDS.

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.

Effects of increased physical activity and/or weight loss diet on serum myokine and adipokine levels in overweight adults with impaired glucose metabolism.

AIM: The purpose of this study was to investigate the changes in serum irisin, fibroblast growth factor-21 (FGF21), visfatin, follistatin like protein-1 (FSTL1), and meteorin-like protein (Metrnl) levels in response to increased physical activity and/or diet interventions in overweight subjects with impaired glucose metabolism (IGM). METHODS: A total of 60 subjects (BMI > 25.0 kg/m2) with IGM were recruited in this single-centered interventional study. Twelve subjects dropped out during the study and the study was completed with 48 patients. Patients were divided into two groups as diet only (DI, n = 24) and diet and physical activity intervention (DPA, n = 24). Patients in DI group received a diet program while DPA group received a diet combined with a physical activity intervention for 12 weeks. Additional 24 healthy subjects were recruited to compare the baseline levels of proteins. Serum protein levels, anthropometric measurements, and biochemical parameters were assessed. RESULTS: Irisin, FGF21, visfatin, and FSTL1 levels significantly decreased in both groups after 12-week intervention (p < 0.001). However, there were no differences in protein levels between DI and DPA groups (p > 0.05). Likewise, the total change in weight was similar in both DI (-4.35 kg) and DPA (-4.85 kg) groups (p > 0.05). A 5% reduction in initial body weight with DPA therapy resulted in a stronger correlation between the changes in irisin, visfatin, and FSTL1 levels and fasting glucose and HbA1c levels. CONCLUSIONS: These results demonstrate that serum irisin, FGF21, visfatin, and FSTL1 levels decreased in response to weight loss interventions. Weight loss induced by DI or DPA therapies had similar lowering effects on these proteins in subjects with IGM, and these myokines might be related to glucose metabolism biomarkers.

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/ ).