Activin A levels in metabolic dysfunction-associated steatotic liver disease associates with fibrosis and the PNPLA3 I148M variant.

BACKGROUND: Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most prevalent chronic liver condition worldwide. There is an urgent need to develop new biomarkers to assess disease severity and to define patients with a progressive phenotype. Activin A is a new promising biomarker with conflicting results about liver fibrosis. In this study we investigate levels of Activin A in patients with biopsy proven MASLD. We assess levels of Activin A in regard to fibrosis stage and genetic variant I148M in the patatin-like phospholipase domain-containing protein 3 (PNPLA3). METHODS: Activin A levels were assessed in plasma samples from patients with biopsy-proven MASLD in a cross-sectional study. All patients were clinically evaluated and the PNPLA3 I148M genotype of the cohort was assessed. FINDINGS: 41 patients were included and 27% of these had advanced fibrosis. In MASLD patients with advanced fibrosis, Activin A levels was higher (p < 0.001) and could classify advanced fibrosis with an AUROC for activin A of 0.836 (p < 0.001). Patients homozygous for PNPLA3 I148M G/G had higher levels of activin A than non-homozygotes (p = 0.027). CONCLUSIONS: Circulating activin A levels were associated with advanced fibrosis and could be a potential blood biomarker for identifying advanced fibrosis in MASLD. Patients with the risk genotype PNPLA3 I148M G/G had higher levels of activin A proposing activin A as a contributor of the transition from simple steatosis to a fibrotic phenotype.

Activin A: a marker of mineral bone disorder in children with chronic kidney disease?

BACKGROUND: Activin A has been shown to enhance osteoclast activity and its inhibition results in bone growth. The potential role of activin A as a marker of chronic kidney disease-mineral bone disease (CKD-MBD) and its relationship with other markers has not been studied in children with CKD. METHODS: A cross sectional study was conducted among 40 children aged 2 to 18 years with CKD (Stage 2 to 5; 10 in each stage) and 40 matched controls. Activin A, cathepsin K, FGF-23, PTH, serum calcium, phosphorous and alkaline phosphatase in both groups were measured and compared. The correlation of activin A and markers of CKD-MBD was studied. A p value of < 0.05 was considered significant. RESULTS: The mean age of children with CKD was 9.30 ± 3.64 years. Mean levels of activin A in cases were 485.55 pg/ml compared to 76.19 pg/ml in controls (p < 0.001). FGF-23 levels in cases were 133.18 pg/ml while in controls it was 6.93 pg/ml (p < 0.001). Mean levels of cathepsin K were also significantly higher in cases as compared to controls. There was a progressive increase in activin A and cathepsin K levels with increasing stage of CKD. Activin A had a significant positive correlation with serum creatinine (r = 0.51; p < 0.001). CONCLUSIONS: Activin A levels progressively rise with advancing CKD stage. These findings suggest that activin A can be a potential early marker of CKD-MBD in children.

Reactivation of herpesvirus type 6 and IgA/IgM-mediated responses to activin-A underpin long COVID, including affective symptoms and chronic fatigue syndrome.

BACKGROUND: Persistent infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), reactivation of dormant viruses, and immune-oxidative responses are involved in long COVID. OBJECTIVES: To investigate whether long COVID and depressive, anxiety, and chronic fatigue syndrome (CFS) symptoms are associated with IgA/IgM/IgG to SARS-CoV-2, human herpesvirus type 6 (HHV-6), Epstein-Barr Virus (EBV), and immune-oxidative biomarkers. METHODS: We examined 90 long COVID patients and ninety healthy controls. We measured serum IgA/IgM/IgG against HHV-6 and EBV and their deoxyuridine 5'-triphosphate nucleotidohydrolase (duTPase), SARS-CoV-2, and activin-A, C-reactive protein (CRP), advanced oxidation protein products (AOPP), and insulin resistance (HOMA2-IR). RESULTS: Long COVID patients showed significant elevations in IgG/IgM-SARS-CoV-2, IgG/IgM-HHV-6, and HHV-6-duTPase, IgA/IgM-activin-A, CRP, AOPP, and HOMA2-IR. Neural network analysis yielded a highly significant predictive accuracy of 80.6% for the long COVID diagnosis (sensitivity: 78.9%, specificity: 81.8%, area under the ROC curve = 0.876); the topmost predictors were as follows: IGA-activin-A, IgG-HHV-6, IgM-HHV-6-duTPase, IgG-SARS-CoV-2, and IgM-HHV-6 (all positively) and a factor extracted from all IgA levels to all viral antigens (inversely). The top 5 predictors of affective symptoms due to long COVID were IgM-HHV-6-duTPase, IgG-HHV-6, CRP, education, IgA-activin-A (predictive accuracy of r = 0.636). The top 5 predictors of CFS due to long COVID were in descending order: CRP, IgG-HHV-6-duTPase, IgM-activin-A, IgM-SARS-CoV-2, and IgA-activin-A (predictive accuracy: r = 0.709). CONCLUSION: Reactivation of HHV-6, SARS-CoV-2 persistence, and autoimmune reactions to activin-A combined with activated immune-oxidative pathways play a major role in the pathophysiology of long COVID as well as the severity of its affective symptoms and CFS.

The Activin/Follistatin Axis Is Severely Deregulated in COVID-19 and Independently Associated With In-Hospital Mortality.

BACKGROUND: Activins are members of the transforming growth factor-ß superfamily implicated in the pathogenesis of several immunoinflammatory disorders. Based on our previous studies demonstrating that overexpression of activin-A in murine lung causes pathology sharing key features of coronavirus disease 2019 (COVID-19), we hypothesized that activins and their natural inhibitor follistatin might be particularly relevant to COVID-19 pathophysiology. METHODS: Activin-A, activin-B, and follistatin were retrospectively analyzed in 574 serum samples from 263 COVID-19 patients hospitalized in 3 independent centers, and compared with demographic, clinical, and laboratory parameters. Optimal scaling with ridge regression was used to screen variables and establish a prediction model. RESULT: The activin/follistatin axis was significantly deregulated during the course of COVID-19, correlated with severity and independently associated with mortality. FACT-CLINYCoD, a scoring system incorporating follistatin, activin-A, activin-B, C-reactive protein, lactate dehydrogenase, intensive care unit admission, neutrophil/lymphocyte ratio, age, comorbidities, and D-dimers, efficiently predicted fatal outcome (area under the curve [AUC], 0.951; 95% confidence interval, .919-.983; P <10-6). Two validation cohorts indicated similar AUC values. CONCLUSIONS: This study demonstrates a link between activin/follistatin axis and COVID-19 mortality and introduces FACT-CLINYCoD, a novel pathophysiology-based tool that allows dynamic prediction of disease outcome, supporting clinical decision making.

Follistatin secretion is enhanced by protein, but not glucose or fat ingestion, in obese persons independently of previous gastric bypass surgery.

Follistatin is secreted from the liver and is involved in the regulation of muscle mass and insulin sensitivity via inhibition of activin A in humans. The secretion of follistatin seems to be stimulated by glucagon and inhibited by insulin, but only limited knowledge on the postprandial regulation of follistatin exists. Moreover, results on postoperative changes after Roux-en-Y gastric bypass (RYGB) are conflicting with reports of increased, unaltered, and lowered fasting concentrations of follistatin. In this study, we investigated postprandial follistatin and activin A concentrations after intake of isocaloric amounts of protein, fat, or glucose in subjects with obesity with and without previous RYGB to explore the regulation of follistatin by the individual macronutrients. Protein intake enhanced follistatin concentrations similarly in the two groups, whereas glucose and fat ingestion did not change postprandial follistatin concentrations. Concentrations of activin A were lower after protein intake compared with glucose intake in RYGB. Glucagon concentrations were also particularly enhanced by protein intake and tended to correlate with follistatin in RYGB. In conclusion, we demonstrated that protein intake, but not glucose or fat, is a strong stimulus for follistatin secretion in subjects with obesity and that this regulation is maintained after RYGB surgery.NEW & NOTEWORTHY Circulating follistatin and activin A were studied after intake of isocaloric protein, fat, or glucose drinks in subjects with obesity with and without previous Roux-en-Y gastric bypass (RYGB). Protein intake enhanced follistatin similarly in both groups, whereas glucose and fat ingestion did not change follistatin. Activin A was lower after protein compared with glucose in RYGB. The novel finding is that protein intake, but neither glucose nor fat, stimulates follistatin secretion independently of previous RYGB.

Effects of Roux-en-Y gastric bypass on circulating follistatin, activin A, and peripheral ActRIIB signaling in humans with obesity and type 2 diabetes.

BACKGROUND: Roux-en-Y gastric bypass (RYGB) surgery is a therapeutic intervention for morbid obesity and type 2 diabetes (T2D) that improves metabolic regulation. Follistatin (Fst) could be implicated in improved glycemia as it is highly regulated by RYGB. However, it is unknown if metabolic status, such as T2D, alters the Fst response to RYGB. In addition, the effect of RYGB on the Fst target, activin A, is unknown in individuals with obesity and T2D, but is needed to interpret the functional effects of altering Fst. Finally, whether Fst-regulated intracellular signaling contributes to beneficial effects of RYGB is undetermined. METHODS: Circulating Fst and activin A were measured before, 1 week, and 1 year after RYGB surgery in a total of 20 individuals with obesity, 10 with normoglycemia (NGT) and 10 with preoperative T2D. Intracellular signaling downstream of the Activin receptor type IIB (ActRIIB) signaling pathway was analyzed in skeletal muscle and adipose tissue. RESULTS: The doubling in circulating Fst observed in subjects with NGT 1-week and 1-year post surgery was absent in T2D. After 1 week, RYGB reduced activin A by 27% (p < 0.001) and 20% (p < 0.01) in subjects with NGT and T2D, respectively; a reduction that tended to be maintained in the subjects with T2D at 1-year post-RYGB (-15%; p = 0.0592). RYGB had no effects on skeletal muscle ActRIIB signaling. In contrast, adipose tissue phosphorylation of SMAD2Ser465/467, p70S6KThr389, S6RPSer235/236, and 4E-BP1Thr37/49 was highly regulated, particularly 1-year post-RYGB (p < 0.05). CONCLUSIONS: In subjects with preoperative T2D, RYGB did not increase circulating Fst contrasting subjects with NGT, while the reduction in activin A was maintained. ActRIIB signaling was upregulated in adipose tissue, but not skeletal muscle, following RYGB in both individuals with NGT and T2D. Our results suggest a role of adipose tissue ActRIIB signaling for the beneficial effects of RYGB surgery.

Serum and urine levels of activin A in primigravidae and multigravidae: a prospective cross-sectional study.

The aim of the present study was to investigate serum and urine levels of activin A in different moments of gestation, in primigravidae and in multigravidae, to understand whether these variables (biological sample and first gestation) affect activin A as a biomarker in pregnancy. We prospectively included 43 pairs of serum and urine samples from 25 women examined at different gestational ages (range 45 to 268 days). In the group of primigravidae (n = 16 samples from 9 participants), there was no significant change in serum activin A levels across gestation. Conversely, the group of multigravidae (n = 27 samples from 16 women) had higher serum activin A levels in the third trimester (2676 ± 840 pg/ml) compared to the first (583 ± 408 pg/ml) and second (1040 ± 384) trimesters (p = .025). Urine activin A concentrations did not differ between the two groups and did not change according to the gestation phase. There was no correlation between serum and urinary levels of activin A (r = 0.149, p = .359). These data suggest that activin A secretion may vary less during the first pregnancy, while urine activin A is unlikely to be a surrogate for the systemic levels of this hormone in pregnant women.

IVIg Promote Cross-Tolerance against Inflammatory Stimuli In Vitro and In Vivo.

IVIg is an approved therapy for immunodeficiency and for several autoimmune and inflammatory diseases. However, the molecular basis for the IVIg anti-inflammatory activity remains to be fully explained and cannot be extrapolated from studies on animal models of disease. We now report that IVIg impairs the generation of human monocyte-derived anti-inflammatory macrophages by inducing JNK activation and activin A production and limits proinflammatory macrophage differentiation by inhibiting GM-CSF-driven STAT5 activation. In vivo, IVIg provokes a rapid increase in peripheral blood activin A, CCL2, and IL-6 levels, an effect that can be recapitulated in vitro on human monocytes. On differentiating monocytes, IVIg promotes the acquisition of altered transcriptional and cytokine profiles, reduces TLR expression and signaling, and upregulates negative regulators of TLR-initiated intracellular signaling. In line with these effects, in vivo IVIg infusion induces a state tolerant toward subsequent stimuli that results in reduced inflammatory cytokine production after LPS challenge in human peripheral blood and significant protection from LPS-induced death in mice. Therefore, IVIg conditions human macrophages toward the acquisition of a state of cross-tolerance against inflammatory stimuli, an effect that correlates with the net anti-inflammatory action of IVIg in vivo.

Circadian rhythm of activin A and related parameters of mineral metabolism in normal and uremic rats.

Activin A is a new fascinating player in chronic kidney disease-mineral and bone disorder (CKD-MBD), which is implicated in progressive renal disease, vascular calcification, and osteodystrophy. Plasma activin A rises early in the progression of renal disease. Disruption of circadian rhythms is related to increased risk of several diseases and circadian rhythms are observed in mineral homeostasis, bone parameters, and plasma levels of phosphate and PTH. Therefore, we examined the circadian rhythm of activin A and CKD-MBD-related parameters (phosphate, PTH, FGF23, and klotho) in healthy controls and CKD rats (5/6 nephrectomy) on high-, standard- and low-dietary phosphate contents as well as during fasting conditions. Plasma activin A exhibited circadian rhythmicity in healthy control rats with fourfold higher values at acrophase compared with nadir. The rhythm was obliterated in CKD. Activin A was higher in CKD rats compared with controls when measured at daytime but not significantly when measured at evening/nighttime, stressing the importance of time-specific reference intervals when interpreting plasma values. Plasma phosphate, PTH, and FGF23 all showed circadian rhythms in control rats, which were abolished or disrupted in CKD. Plasma klotho did not show circadian rhythm. Thus, the present investigation shows, for the first time, circadian rhythm of plasma activin A. The rhythmicity is severely disturbed by CKD and is associated with disturbed rhythms of phosphate and phosphate-regulating hormones PTH and FGF23, indicating that disturbed circadian rhythmicity is an important feature of CKD-MBD.

Activin-A is elevated in patients with thalassemia major and double heterozygous sickle cell/beta-thalassemia and correlates with markers of hemolysis and bone mineral density.

Despite the advances in the management of hemoglobinopathies, further insight into disease pathophysiology is necessary to improve our therapeutic approach. Activin-A has emerged as a regulator of erythropoiesis and bone turnover in malignant disorders; however, clinical data in hemoglobinopathies are currently scarce. Thus, we aimed to investigate the role of activin-A among hemoglobinopathy patients and evaluate the rationale of its targeting. Circulating levels of activin-A were measured in patients (n = 227) with beta-thalassemia major (TM) (n = 58), beta-thalassemia intermedia (TI) (n = 43), double heterozygous sickle cell/beta-thalassemia (HbS/beta-thal) (n = 109), or homozygous sickle cell disease (n = 17), and we explored possible correlations with clinical and laboratory data. Seventeen age- and gender-matched, healthy individuals served as controls. Bone marrow density (BMD) was determined using dual-energy X-ray absorptiometry. TM and HbS/beta-thal patients had elevated activin-A compared to controls (p = 0.041 and p = 0.038, respectively). In TM patients, high circulating activin-A showed strong correlations with hemolysis markers, namely reticulocyte count (p = 0.011) and high lactate dehydrogenase (LDH; p = 0.024). Similarly, in HbS/beta-thal patients, activin-A showed positive correlations with indirect bilirubin (p < 0.001), ferritin (p = 0.005), and LDH (p = 0.044). High activin-A correlated with low Z-score of both lumbar spine BMD in TI patients (p < 0.01) and femoral neck BMD in TM patients (p < 0.01). Serum activin-A is elevated in patients with TM and HbS/beta-thal and correlates with markers of hemolysis and low BMD. These data support a role of activin-A in the biology of these disorders and provide further rationale for the broader clinical development of activin-A inhibitors in this setting.

Circulating Activin A Is a Surrogate for the Incidence of Diastolic Dysfunction and Heart Failure in Patients With Preserved Ejection Fraction.

BACKGROUND: Diastolic dysfunction (DD) is a characteristic of heart failure with preserved ejection fraction (HFpEF), which is thought to be caused by cardiac hypertrophy or fibrosis. Activin A is involved in the inflammatory response and myocardial fibrosis, but the relationship between the activin A level and DD remains unclear.Methods and Results:A total of 209 patients with stable angina were enrolled. Serum activin A levels were assessed, and echocardiography and cross-sectional analysis were performed. Among the subjects (65% male; mean age, 70±13 years), 84 (40%) subjects had DD. The subjects were divided into tertiles based on activin A levels. Patients in the high activin A group had enhanced left ventricular mass indexes, medial E/e' ratios, left atrial diameter, and right ventricular systolic pressure compared with those in the lower activin A groups (all P<0.001). Prevalence of DD (P=0.001), HFpEF at enrollment (P=0.007), and the composite endpoints including new-onset heart failure (HF) or death within 3 years (P<0.001) correlated positively with high activin A levels. After adjusting for confounding factors, high activin A levels remained significantly associated with DD (P=0.036) and the composite endpoints (P=0.012). CONCLUSIONS: Enhanced serum activin A levels were associated with the incidence of DD and development of HF.

Serum bone markers in ROD patients across the spectrum of decreases in GFR: Activin A increases before all other markers
.

INTRODUCTION: Renal osteodystrophy (ROD) develops early in chronic kidney disease (CKD) and progresses with loss of kidney function. While intact parathyroid hormone (PTH), 1,25-dihydroxyvitamin D3 (1,25D), and fibroblast growth factor-23 (FGF-23) levels are usually considered the primary abnormalities in ROD development, the role of serum activin A elevations in CKD and its relationships to ROD have not been explored. The aims of this study were to evaluate serum activin A at different CKD stages, and to establish the relationships between activin A, bone biomarkers, and bone histomorphometric parameters. MATERIALS AND METHODS: 104 patients with CKD stages 2 - 5D underwent bone biopsies. We measured in the serum activin A, BSAP, DKK1, FGF-23, α-Klotho, intact PTH, sclerostin, TRAP-5b, and 1,25D. Biochemical results were compared across CKD stages and with 19 age-matched controls with normal kidney function. RESULTS: Median activin A levels were increased in all stages of CKD compared to controls from 544 pg/mL in CKD 2 (431 - 628) to 1,135 pg/mL in CKD 5D (816 - 1,456), compared to 369 pg/mL in controls (316 - 453, p < 0.01). The increase of activin A in CKD 2 (p = 0.016) occurred before changes in the other measured biomarkers. Activin A correlated with intact PTH and FGF-23 (r = 0.65 and 0.61; p < 0.01) and with histomorphometric parameters of bone turnover (BFR/BS, Acf, ObS/BS and OcS/BS; r = 0.47 - 0.52; p < 0.01). These correlations were comparable to those found with intact PTH and FGF-23. CONCLUSION: Serum activin A levels increase starting at CKD 2 before elevations in intact PTH and FGF-23. Activin A correlates with bone turnover similar to intact PTH and FGF-23. These findings suggest a role for activin A in early development of ROD.

Diagnostic and prognostic values of serum activin-a levels in patients with acute respiratory distress syndrome.

BACKGROUND: We aimed to evaluate whether serum activin-A levels are elevated and have any value in predicting severity and prognosis in acute respiratory distress syndrome (ARDS). METHODS: Retrospective cohort study was performed with patients who were admitted to MICU with diagnosis of ARDS and have serum samples stored within 48 h of Intensive care unit (ICU) admission between March 2013 and December 2016 at a single tertiary referral hospital. Serum activin-A levels were measured with ELISA kit, and were compared with those of normal healthy control and non-ARDS sepsis patients. RESULTS: Total 97 ARDS patients were included for the study. Levels of Activin-A were elevated in ARDS patients compared to those of healthy controls (Log-transformed activin-A levels 2.89 ± 0.36 vs. 2.34 ± 0.11, p < 0.001, absolute activin-A levels 1525.6 ± 1060.98 vs. 225.9 ± 30.1, p = 0.016) and non-ARDS sepsis patients (Log-transformed activin-A levels 2.89 ± 0.36 vs. 2.73 ± 0.34, p = 0.002, Absolute activin-A levels 1525.6 ± 1060.98 vs. 754.8 ± 123.5 pg/mL, p = 0.036). When excluding five outliers with extremely high activin-A levels, activin-A showed statistically significant correlation with in-hospital mortalities (In-hospital survivors 676.2 ± 407 vs. non-survivors 897.9 ± 561.9 pg/mL, p = 0.047). In predicting in-hospital mortality, serum activin-A concentrations showed superior area under curve compared to that of Acute physiologic and chronic health evaluation II scores (0.653; 95% CI [0541, 0.765] vs. 0.591, 95% CI [0.471, 0.710]). With cut-off level of 708 pg/mL, those with high serum activin-A levels had more than twofold increased risk of in-hospital mortalities. However, those relations were missing when outliers were in. CONCLUSIONS: Serum activin-A levels in ARDS patients are elevated. However, its levels are weakly associated with ARDS outcomes.

Weighting of orthostatic intolerance time measurements with standing difficulty score stratifies ME/CFS symptom severity and analyte detection.

BACKGROUND: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is clinically defined and characterised by persistent disabling tiredness and exertional malaise, leading to functional impairment. METHODS: This study introduces the weighted standing time (WST) as a proxy for ME/CFS severity, and investigates its behaviour in an Australian cohort. WST was calculated from standing time and subjective standing difficulty data, collected via orthostatic intolerance assessments. The distribution of WST for healthy controls and ME/CFS patients was correlated with the clinical criteria, as well as pathology and cytokine markers. Included in the WST cytokine analyses were activins A and B, cytokines causally linked to inflammation, and previously demonstrated to separate ME/CFS from healthy controls. Forty-five ME/CFS patients were recruited from the CFS Discovery Clinic (Victoria) between 2011 and 2013. Seventeen healthy controls were recruited concurrently and identically assessed. RESULTS: WST distribution was significantly different between ME/CFS participants and controls, with six diagnostic criteria, five analytes and one cytokine also significantly different when comparing severity via WST. On direct comparison of ME/CFS to study controls, only serum activin B was significantly elevated, with no significant variation observed for a broad range of serum and urine markers, or other serum cytokines. CONCLUSIONS: The enhanced understanding of standing test behaviour to reflect orthostatic intolerance as a ME/CFS symptom, and the subsequent calculation of WST, will encourage the greater implementation of this simple test as a measure of ME/CFS diagnosis, and symptom severity, to the benefit of improved diagnosis and guidance for potential treatments.

Placental and maternal serum activin A in spontaneous and induced labor in late-term pregnancy.

PURPOSE: Feto-placental unit represents an important source of activin A, a member of transforming growth factors-ß involved in the mechanisms of labor. No evidences are available on activin A in pregnancies beyond 41 weeks of gestation, where induction of labor is often required. The present study aimed to evaluate activin A maternal serum levels and placental mRNA expression in term and late-term pregnancy, with spontaneous or induced labor, and its possible role to predict the response to labor induction. METHODS: Maternal serum samples and placental specimens were collected from women with singleton pregnancy admitted for either term spontaneous labor (n = 23) or induction of labor for late-term pregnancy (n = 41), to evaluate activin A serum levels and placental mRNA expression. Univariate and multivariate analyses on activin A serum levels, maternal clinical parameters, and cervical length were conducted in women undergoing induction of labor. RESULTS: Maternal serum activin A levels and placental activin A mRNA expression in late-term pregnancies were significantly higher than at term. Late-term pregnancies who did not respond to induction of labor showed significantly lower levels of activin A compared to responders. The combination of serum activin A and cervical length achieved a sensitivity of 100% and a specificity of 93.55% for the prediction of successful induction. CONCLUSION: Late-term pregnancy is characterized by hyperexpression of placental activin A and increased maternal activin A secretion. By combining maternal serum activin A levels with cervical length, a good predictive model for the response to induction of labor was elaborated.

Correlation of concentrations of activin A with occurrence and severity of knee osteoarthritis.

BACKGROUND: Activin A plays as an anticatabolic autocrine cytokine in articular cartilage. Thus, this study aims to evaluate whether activin Aconcentration is correlated with the occurrence and severity of knee osteoarthritis (OA). METHODS: A total of 210 knee OA patients and 150 healthy controls were enrolled in this cross-sectional study, to evaluate the severity of OA by Kellgren-Lawrence (KL) grading method. RESULTS: It was found that the concentration of activin A in knee OA group was higher than that in healthy subjects. Furthermore, results of of activin A concentration in serum and synovial fluid (SF) suggested that activin A concentration was the highest in Kellgren-Lawrence (KL) grade 4, and the lowest in KL grade 2. Concentrations of activin A in serum and SF showed significant correlation with disease severity measured by KL grading criteria. CONCLUSIONS: It was indicated that concentrations of activin A in serum and SF showed a positive correlation with the occurrence and severity of knee OA.

Activin B is a novel biomarker for chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) diagnosis: a cross sectional study.

BACKGROUND: Investigations of activin family proteins as serum biomarkers for chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME). CFS/ME is a disease with complex, wide-ranging symptoms, featuring persistent fatigue of 6 months or longer, particularly post exertion. No definitive biomarkers are available. METHODS: A cross-sectional, observational study of CFS/ME patients fulfilling the 2003 Canadian Consensus Criteria, in parallel with healthy non-fatigued controls, was conducted. Comparisons with a previously defined activin reference population were also performed. For the total study cohort the age range was 18-65 years with a female: male participant ratio of greater than 3:1. All participants were assessed via a primary care community clinic. Blood samples were collected for pathology testing after physical examination and orthostatic intolerance assessment. Cytokines, activin A, activin B and follistatin were also measured in sera from these samples. All data were compared between the CFS/ME and control cohorts, with the activins and follistatin also compared with previously defined reference intervals. RESULTS: Serum activin B levels for CFS/ME participants were significantly elevated when compared to the study controls, as well as the established reference interval. Serum activin A and follistatin were within their normal ranges. All routine and special pathology markers were within the normal laboratory reference intervals for the total study cohort, with no significant differences detected between CFS/ME and control groups. Also, no significant differences were detected for IL-2, IL-4, IL-6, IL-10, IL-17A, TNF or IFN-gamma. CONCLUSION: Elevated activin B levels together with normal activin A levels identified patients with the diagnostic symptoms of CFS/ME, thus providing a novel serum based test. The activins have multiple physiological roles and capture the diverse array of symptoms experienced by CFS/ME patients.

Suppression of Sertoli cell tumour development during the first wave of spermatogenesis in inhibin α-deficient mice.

A dynamic partnership between follicle-stimulating hormone (FSH) and activin is required for normal Sertoli cell development and fertility. Disruptions to this partnership trigger Sertoli cells to deviate from their normal developmental pathway, as observed in inhibin α-knockout (Inha-KO) mice, which feature Sertoli cell tumours in adulthood. Here, we identified the developmental windows by which adult Sertoli cell tumourigenesis is most FSH sensitive. FSH was suppressed for 7 days in Inha-KO mice and wild-type littermates during the 1st, 2nd or 4th week after birth and culled in the 5th week to assess the effect on adult Sertoli cell development. Tumour growth was profoundly reduced in adult Inha-KO mice in response to FSH suppression during Weeks 1 and 2, but not Week 4. Proliferative Sertoli cells were markedly reduced in adult Inha-KO mice following FSH suppression during Weeks 1, 2 or 4, resulting in levels similar to those in wild-type mice, with greatest effect observed at the 2 week time point. Apoptotic Sertoli cells increased in adult Inha-KO mice after FSH suppression during Week 4. In conclusion, acute FSH suppression during the 1st or 2nd week after birth in Inha-KO mice profoundly suppresses Sertoli cell tumour progression, probably by inhibiting proliferation in the adult, with early postnatal Sertoli cells being most sensitive to FSH action.

Selective protein depletion impairs bone growth and causes liver fatty infiltration in female rats: prevention by Spirulina alga.

Chronic protein malnutrition leads to child mortality in developing countries. Spirulina alga (Spi), being rich in protein and growing easily, is a good candidate as supplementation. We showed that Spi completely prevents bone growth retardation and liver disturbances observed in young rats fed a low protein diet. This supports Spi as a useful source of vegetable protein to fight against protein malnutrition. INTRODUCTION: Chronic malnutrition is a main factor of child mortality in developing countries. A low protein diet impairs whole-body growth and leads to fatty liver in growing rats. Spi has great potential as a supplementation as it has a 60 % protein content and all essential amino acids. However, its specific impact on bone growth and the related secretion of hepatokines have not yet been studied. METHODS: To address this question, 6-week-old female rats were fed isocaloric diets containing 10 % casein, 5 % casein, or 5 % casein + 5 % protein from Spi during 9 weeks. Changes in tibia geometry, microarchitecture, BMC, BMD, and biomechanical properties were analyzed. Serum IGF-I, FGF21, follistatin, and activin A were assessed as well as their hepatic gene expressions in addition to those of Sirt1, Ghr, and Igf1r. Hepatic fat content was also assessed. RESULTS: A low protein diet altered bone geometry and reduced proximal tibia BMD and trabecular bone volume. In addition, it increased hepatic fat content and led to hepatic GH resistance by decreasing serum IGF-I and increasing serum FGF21 without altering serum activin A and follistatin. Spi prevented low protein diet-induced bone, hepatic, and hormonal changes, and even led to higher biomechanical properties and lower hepatic fat content in association with specific InhbA and Follistatin expression changes vs. the 10 % casein group. CONCLUSIONS: Altogether our results demonstrate the preventive impact of Spi on bone growth delay and hepatic GH resistance in conditions of isocaloric dietary protein deficiency.

Clinical Impact of Cystatin C/Cathepsin L and Follistatin/Activin A Systems in Breast Cancer Progression: A Preliminary Report.

This study was directed to assess the clinical impact of the circulating cathepsin L, cystatin C, activin A, and follistatin in breast cancer patients. The serum concentrations of these molecules were determined by immunoenzymatic assays, and their association with some clinico-pathological parameters of breast cancer progression was evaluated. Our results identified cystatin C and activin A as predictive markers for the presence of breast cancer and bone metastasis, respectively. Therefore, these proteins may have a clinical role as circulating biomarkers in the diagnosis and therapeutic monitoring of breast cancer patients.