Activin A Modulates Inflammation in Acute Pancreatitis and Strongly Predicts Severe Disease Independent of Body Mass Index.

INTRODUCTION: Acute pancreatitis (AP) is a healthcare challenge with considerable mortality. Treatment is limited to supportive care, highlighting the need to investigate disease drivers and prognostic markers. Activin A is an established mediator of inflammatory responses, and its serum levels correlate with AP severity. We hypothesized that activin A is independent of body mass index (BMI) and is a targetable promoter of the AP inflammatory response. METHODS: We assessed whether BMI and serum activin A levels are independent markers to determine disease severity in a cohort of patients with AP. To evaluate activin A inhibition as a therapeutic, we used a cerulein-induced murine model of AP and treated mice with activin A-specific neutralizing antibody or immunoglobulin G control, both before and during the development of AP. We measured the production and release of activin A by pancreas and macrophage cell lines and observed the activation of macrophages after activin A treatment. RESULTS: BMI and activin A independently predicted severe AP in patients. Inhibiting activin A in AP mice reduced disease severity and local immune cell infiltration. Inflammatory stimulation led to activin A production and release by pancreas cells but not by macrophages. Macrophages were activated by activin A, suggesting activin A might promote inflammation in the pancreas in response to injury. DISCUSSION: Activin A provides a promising therapeutic target to interrupt the cycle of inflammation and tissue damage in AP progression. Moreover, assessing activin A and BMI in patients on hospital admission could provide important predictive measures for screening patients likely to develop severe disease.

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.

Effects of elastic band resistance training and nutritional supplementation on muscle quality and circulating muscle growth and degradation factors of institutionalized elderly women: the Vienna Active Ageing Study (VAAS).

PURPOSE: Regular resistance exercise training and a balanced diet may counteract the age-related muscular decline on a molecular level. The aim of this study was to investigate the influence of elastic band resistance training and nutritional supplementation on circulating muscle growth and degradation factors, physical performance and muscle quality (MQ) of institutionalized elderly. METHODS: Within the Vienna Active Ageing Study, 91 women aged 83.6 (65.0-92.2) years were randomly assigned to one of the three intervention groups (RT, resistance training; RTS, resistance training plus nutritional supplementation; CT, cognitive training). Circulating levels of myostatin, activin A, follistatin, IGF-1 and GDF-15, as well as MQ and functional parameters were tested at baseline as well as after 3 and 6 months of intervention. RESULTS: MQ of lower extremities significantly increased in the RT group (+14 %) and RTS group (+12 %) after 6 months. Performance improved in the RT and RTS groups for chair stand test (RT: +18 %; RTS: +15 %). Follistatin increased only in the RT group (+18 %) in the latter phase of the intervention, accompanied by a decrease in the activin A-to-follistatin ratio (-7 %). IGF-1, myostatin and GDF-15 levels were not affected by the intervention. CONCLUSION: Our data confirm that strength training improves physical performance and MQ even in very old institutionalized women. This amelioration appears to be mediated by blocking muscle degradation pathways via follistatin rather than inducing muscle growth through the IGF-1 pathway. As plasma levels of biomarkers reflect an overall status of various organ systems, future studies of tissue levels are suggested.

Neuroendocrine control of FSH secretion: IV. Hypothalamic control of pituitary FSH-regulatory proteins and their relationship to changes in FSH synthesis and secretion.

The current dogma is that the differential regulation of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) synthesis and secretion is modulated by gonadotropin-releasing hormone (GnRH) pulse frequency and by changes in inhibins, activins, and follistatins both at the pituitary and at the peripheral level. To date no studies have looked at the overlapping function of these regulators in a combined setting. We tested the hypothesis that changes in GnRH pulse frequency alter the relative abundance of these regulators at the pituitary and peripheral levels in a manner consistent with changes in pituitary and circulating concentrations of FSH; that is, an increase in FSH will be accompanied by increased stimulatory input (activin) and/or reduced follistatin and inhibin. Ovariectomized ewes were subjected to a combination hypothalamic pituitary disconnection (HPD)-hypophyseal portal blood collection procedure. Hypophyseal portal and jugular blood samples were collected for a 6-h period from non-HPD ewes, HPD ewes, or HPD ewes administered GnRH hourly or every 3 h for 4 days. In the absence of endogenous hypothalamic and ovarian hormones that regulate gonadotropin secretion, 3-hourly pulses of GnRH increased pituitary content of FSH more than hourly GnRH, although these differences were not evident in the peripheral circulation. The results failed to support the hypothesis in that the preferential increase of pituitary content of FSH by the lower GnRH pulse frequency could be explained by changes in the pituitary content of inhibin A, follistatin, or activin B. Perhaps the effects of GnRH pulse frequency on FSH is due to changes in the balance of free versus bound amounts of these FSH regulatory proteins or to the involvement of other regulators not monitored in this study.

[Regulation and control of wenshen yangxue granule combined with clomifene citrate on INH-ACT-FS system in patients with follicular maldevelopment infertility].

OBJECTIVE: To observe the clinical curative effect of Wenshen Yangxue Granule (WSYXG) combined with clomifene citrate (CC) in treating follicular maldevelopment (FM) infertility, and to explore its possible action channels. METHODS: Ninety patients with FM of Shen-deficiency blood stasis syndrome were randomly assigned to 3 groups, i.e., the Chinese medicine group (CMG, treated with WXYXG), the Western medicine group (WMG, treated with CC), and the combination group of Chinese medicine and Western medicine (CG, treated with both WSYXG and CC), 30 cases in each group. Three menstrual cycles were totally observed. Serum levels of luteinizing hormone (LH), follicle stimulating hormone (FSH), estradiol (E2 ), inhibin B (INHB), activin A (ACTA), and follistatin (FS) were tested before and after treatment, and the ovulation was monitored and their basic body temperature measured. RESULTS: There was no statistical difference in clinical efficacy among the three groups (P> 0.05). Better effects on the Chinese medicine syndrome efficacy, the ovulation rate, and the endometrium thickness on the ovulation day were shown in CMG and CG than in WMG, showing statistical difference (P < 0.05). The E2 level increased on the third day of the first menstrual cycle in CG when compared with before treatment. On the 10th day of the 1st menstrual cycle, the INHB and FS increased and the ACTA decreased, showing statistical difference (P < 0.05). On the 10th day of the 3rd menstrual cycle the serum LH level decreased more obviously in CG than in WMG, showing statistical difference (P < 0.05). On the 3rd day of the 3rd menstrual cycle in CG, the INHB was negatively correlated with FSH (r = -0.492,P < 0.01), and INHB on the 10th day was positively correlated with E2 and FS (r = 0.682, 0.772, P < 0.01), and negatively correlated with ACTA on the 10th day (r = -0.635, P < 0.01). CONCLUSION: WSYXG combined with CC could improve Chinese medicine syndrome, regulate the expressions of FM patients' ovary local factors INHB, ACTA and FS, improve the condition of ovary functions, and control the follicle development.

New markers of neonatal neurology.

Hypoxia-ischemia (H-I) constitutes the main phenomenon responsible for brain-blood barrier permeability modifications leading to cerebral vascular auto-regulation loss in newborns. Hypotension, cerebral ischemia, and reperfusion are the main events involved in vascular auto-regulation loss leading to cell death and tissue damage. Reperfusion could be critical since organ damage, particularly of the brain, may be amplified during this period. An exaggerated activation of vasoactive agents, of calcium mediated effects could be responsible for reperfusion injury (R-I), which, in turns, leads to cerebral hemorrhage and damage. These phenomena represent a common repertoire in newborns complicated by perinatal acute or chronic hypoxia treated by risky procedures such as mechanical ventilation, nitric oxide supplementation, brain cooling, and extracorporeal membrane oxygenation (ECMO). Despite accurate monitoring, the post-insult period is crucial, as clinical symptoms and standard monitoring parameters may be silent at a time when brain damage is already occurring and the therapeutic window for pharmacological intervention is limited. Therefore, the measurement of circulating biochemical markers of brain damage, such as vasoactive agents and nervous tissue peptides is eagerly awaited in clinical practice to detect high risk newborns. The present review is aimed at investigating the role of biochemical markers such as adrenomedullin, a vasoactive peptide; S100B, a calcium binding protein, activin A, a glycoprotein, in the cascade of events leading to I-R injury in newborns complicated by perinatal asphyxia.

Busulfan induces activin A expression in vitro and in vivo: a possible link to venous occlusive disease.

PURPOSE: Hepatic venous occlusive disease is a severe side effect after administration of busulfan before hematopoietic stem cell transplantation. The syndrome is characterized by liver enlargement, fluid retention, jaundice, and weight gain. Endothelial injury has been described as the precipitating factor. The link between busulfan administration and endothelial damage has not been established thus far. METHODS: Complementary deoxyribonucleic acid expression arrays were used to screen for busulfan responsive genes in ECV304 cells. Specific messenger ribonucleic acid and protein levels were examined by real-time polymerase chain reaction and enzyme-linked immunosorbent assay, respectively. Serum samples of 15 pediatric patients with leukemia were analyzed for busulfan and cytokine levels. RESULTS: We identified a member of the transforming growth factor beta superfamily, activin A, to be induced in the human cell line ECV304 after exposure to busulfan in a time- and concentration-dependent manner. Maximum effects were observed at 120 and 168 hours for activin A messenger ribonucleic acid and protein, respectively. Preincubation with the protein kinase C inhibitor bisindolylmaleimide I (10 nmol/L) abolished activin A induction by busulfan (P <.05). Activin receptors were detected in ECV304. Both tissue factor and cyclooxygenase 2 were significantly induced by busulfan (P <.05). In a parallel in vivo study a significant increase in serum activin A concentration was found 4.5 hours after the second dose of busulfan. CONCLUSION: The data demonstrate that busulfan induces activin A both in vitro and in vivo. In view of the multiple targets of activin A (inflammation, proliferation, apoptosis, and coagulation), these findings may be of relevance to our understanding of venous occlusive disease.