-
Journal of Mother and Child Jun 2023Within the endocrine-paracrine signalling network at the maternal-foetal interface, the activin-inhibin-follistatin system modulates extravillous trophoblast invasion,... (Review)
Review
BACKGROUND
Within the endocrine-paracrine signalling network at the maternal-foetal interface, the activin-inhibin-follistatin system modulates extravillous trophoblast invasion, suggesting a potential role in preeclampsia pathogenesis. This study aimed to compile the evidence published in the last decade regarding the variation in maternal serum activins, inhibin- and follistatin-related proteins in preeclamptic pregnancies compared to healthy pregnancies, and to discuss their role in predicting and understanding the pathophysiology of preeclampsia.
MATERIAL AND METHODS
A scoping review was conducted in MEDLINE, EMBASE and LILACS databases to identify studies published within the last ten years (2012-2022).
RESULTS
Thirty studies were included. None of the studies addressed maternal serum changes of isoforms different from activin A, inhibin A, follistatin, and follistatin-like 3. Sixteen studies evaluated the potential of these isoforms in predicting preeclampsia through the area under the curve from a receiver operating characteristic curve.
CONCLUSIONS
In preeclampsia, inhibin A is upregulated in all trimesters, whereas activin A increases exclusively in the late second and third trimesters. Serum follistatin levels are reduced in women with preeclampsia during the late second and third trimesters. However, changes in follistatin-like 3 remain inconclusive. Inhibin A and activin A can potentially serve as biomarkers of early-onset preeclampsia based on the outcomes of the receiver operating characteristic curve analysis. Further investigations are encouraged to explore the feasibility of quantifying maternal serum levels of activin A and inhibin A as a clinical tool in early preeclampsia prediction.
Topics: Pregnancy; Female; Humans; Follistatin; Follistatin-Related Proteins; Pre-Eclampsia; Inhibins; Activins
PubMed: 37595293
DOI: 10.34763/jmotherandchild.20232701.d-23-00002 -
Cytokine & Growth Factor Reviews Dec 2015The TGF-β superfamily consists of a large group of pleiotropic cytokines that are involved in the regulation of many developmental, physiological and pathological... (Review)
Review
The TGF-β superfamily consists of a large group of pleiotropic cytokines that are involved in the regulation of many developmental, physiological and pathological processes. Dendritic cells are antigen-presenting cells that play a key role in innate and adaptive immune responses. Dendritic cells have a complex relationship with the TGF-β cytokine superfamily being both source and targets for many of these cytokines. Some TGF-β family members are expressed by dendritic cells and modulate immune responses, for instance through the induction of T cell polarization. Others play a crucial role in the development and function of the different dendritic cell subsets. This review summarizes the current knowledge on the role of TGF-β family cytokines in dendritic cell biology, focusing on TGF-β as well as on other, less characterized, members of these important immune mediators.
Topics: Activins; Bone Morphogenetic Proteins; Dendritic Cells; Gene Expression Regulation; Humans; Killer Cells, Natural; Ligands; Signal Transduction; T-Lymphocytes; Transforming Growth Factor beta
PubMed: 26115564
DOI: 10.1016/j.cytogfr.2015.06.002 -
Bone Jun 2019Chondrocyte proliferation and differentiation are crucial for endochondral ossification and strictly regulated by numerous signaling molecules and transcription factors,...
Chondrocyte proliferation and differentiation are crucial for endochondral ossification and strictly regulated by numerous signaling molecules and transcription factors, but the hierarchical regulatory network remains to be deciphered. The present study emphasized the interplay of Activin A, Foxa, Notch and Shh signaling in the proliferation and differentiation of antler chondrocytes. We found that Activin A promoted chondrocyte proliferation and differentiation, and accelerated the transition of cell cycle from G1 into S phase along with the activation of Notch and Shh signaling whose blockage attenuated above function of Activin A. Inhibition of Notch pathway by DAPT led to a significant reduction in the expression of Shh signaling molecules, whereas addition of exogenous rShh rescued the delayed onset of chondrocyte proliferation and differentiation elicited by DAPT, indicating that Notch pathway is upstream of Shh signaling. Further analysis evidenced that DAPT attenuated the activation of Activin A on Shh signaling. Simultaneously, Foxa transcription factors were downstream targets of Shh signaling in chondrocyte differentiation. Moreover, Shh pathway played an important role in the crosstalk between Activin A-Notch signaling and Foxa. Collectively, Shh signaling may act downstream of Notch pathway to mediate the effects of Activin A on the proliferation and differentiation of antler chondrocytes through targeting Foxa.
Topics: Activins; Animals; Cell Differentiation; Cell Proliferation; Chondrocytes; Flow Cytometry; Hedgehog Proteins; RNA Interference; Real-Time Polymerase Chain Reaction; Receptors, Notch; Signal Transduction
PubMed: 30928640
DOI: 10.1016/j.bone.2019.03.036 -
American Journal of Obstetrics and... Jan 2015Clinical management of preeclampsia has remained unchanged for almost 5 decades. We now understand that maternal endothelial dysfunction likely arises because of...
OBJECTIVE
Clinical management of preeclampsia has remained unchanged for almost 5 decades. We now understand that maternal endothelial dysfunction likely arises because of placenta-derived vasoactive factors. Activin A is one such antiangiogenic factor that is released by the placenta and that is elevated in maternal serum in women with preeclampsia. Whether activin has a role in the pathogenesis of preeclampsia is not known.
STUDY DESIGN
To assess the effects of activin on endothelial cell function, we cultured human umbilical vein endothelial cells in the presence of activin or serum from normal pregnant women or pregnant women with preeclampsia, with or without follistatin, a functional activin antagonist or apocynin, a NADPH oxidase (Nox2) inhibitor. We also administered activin to pregnant C57Bl6 mice, with or without apocynin, and studied maternal and fetal outcomes. Last, we assessed endothelial cell Nox2 and nitric oxide synthase expression in normal pregnant women and pregnant women with preeclampsia.
RESULTS
Activin and preeclamptic serum induced endothelial cell oxidative stress by Nox2 up-regulation and endothelial cell dysfunction, which are effects that are mitigated by either follistatin or apocynin. The administration of activin to pregnant mice induced endothelial oxidative stress, hypertension, proteinuria, fetal growth restriction, and preterm littering. Apocynin prevented all of these effects. Compared with normal pregnant women, women with preeclampsia had increased endothelial Nox2 expression.
CONCLUSION
An activin-Nox2 pathway is a likely link between an injured placenta, endothelial dysfunction, and preeclampsia. This offers opportunities that are not novel therapeutic approaches to preeclampsia.
Topics: Activins; Animals; Cells, Cultured; Endothelial Cells; Endothelium, Vascular; Female; Humans; In Vitro Techniques; Mice; Mice, Inbred C57BL; NADPH Oxidases; Oxidative Stress; Pre-Eclampsia; Pregnancy; Up-Regulation
PubMed: 25046804
DOI: 10.1016/j.ajog.2014.07.021 -
PLoS Genetics Dec 2022Activin and inhibin are both dimeric proteins sharing the same β subunits that belong to the TGF-β superfamily. They are well known for stimulating and inhibiting...
Activin and inhibin are both dimeric proteins sharing the same β subunits that belong to the TGF-β superfamily. They are well known for stimulating and inhibiting pituitary FSH secretion, respectively, in mammals. In addition, activin also acts as a mesoderm-inducing factor in frogs. However, their functions in development and reproduction of other species are poorly defined. In this study, we disrupted all three activin/inhibin β subunits (βAa, inhbaa; βAb, inhbab; and βB, inhbb) in zebrafish using CRISPR/Cas9. The loss of βAa/b but not βB led to a high mortality rate in the post-hatching stage. Surprisingly, the expression of fshb but not lhb in the pituitary increased in the female βA mutant together with aromatase (cyp19a1a) in the ovary. The single mutant of βAa/b showed normal folliculogenesis in young females; however, their double mutant (inhbaa-/-;inhbab-/-) showed delayed follicle activation, granulosa cell hypertrophy, stromal cell accumulation and tissue fibrosis. The ovary of inhbaa-/- deteriorated progressively after 180 dpf with reduced fecundity and the folliculogenesis ceased completely around 540 dpf. In addition, tumor- or cyst-like tissues started to appear in the inhbaa-/- ovary after about one year. In contrast to females, activin βAa/b mutant males showed normal spermatogenesis and fertility. As for activin βB subunit, the inhbb-/- mutant exhibited normal folliculogenesis, spermatogenesis and fertility in both sexes; however, the fecundity of mutant females decreased dramatically at 270 dpf with accumulation of early follicles. In summary, the activin-inhibin system plays an indispensable role in fish reproduction, in particular folliculogenesis and ovarian homeostasis.
Topics: Animals; Female; Inhibins; Inhibin-beta Subunits; Zebrafish; Activins; Reproduction; Mammals
PubMed: 36469526
DOI: 10.1371/journal.pgen.1010523 -
Journal of Endocrinological... Feb 2018Feto-placental unit represents an important source of activin A, a member of transforming growth factors-β involved in the mechanisms of labor. No evidences are...
PURPOSE
Feto-placental unit represents an important source of activin A, a member of transforming growth factors-β 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.
Topics: Activins; Adult; Biomarkers; Female; Humans; Labor Onset; Labor Stage, First; Labor, Induced; Placenta; Pregnancy; Prospective Studies
PubMed: 28612286
DOI: 10.1007/s40618-017-0640-z -
MBio Mar 2024Activin A strongly influences immune responses; yet, few studies have examined its role in infectious diseases. We measured serum activin A levels in two independent...
UNLABELLED
Activin A strongly influences immune responses; yet, few studies have examined its role in infectious diseases. We measured serum activin A levels in two independent tuberculosis (TB) patient cohorts and in patients with pneumonia and sarcoidosis. Serum activin A levels were increased in TB patients compared to healthy controls, including those with positive tuberculin skin tests, and paralleled severity of disease, assessed by X-ray scores. In pneumonia patients, serum activin A levels were also raised, but in sarcoidosis patients, levels were lower. To determine whether blockade of the activin A signaling axis could play a functional role in TB, we harnessed a soluble activin type IIB receptor fused to human IgG1 Fc, ActRIIB-Fc, as a ligand trap in a murine TB model. The administration of ActRIIB-Fc to -infected mice resulted in decreased bacterial loads and increased numbers of CD4 effector T cells and tissue-resident memory T cells in the lung. Increased frequencies of tissue-resident memory T cells corresponded with downregulated T-bet expression in lung CD4 and CD8 T cells. Altogether, the results suggest a disease-exacerbating role of ActRIIB signaling pathways. Serum activin A may be useful as a biomarker for diagnostic triage of active TB or monitoring of anti-tuberculosis therapy.
IMPORTANCE
Tuberculosis remains the leading cause of death by a bacterial pathogen. The etiologic agent of tuberculosis, , can remain dormant in the infected host for years before causing disease. Significant effort has been made to identify biomarkers that can discriminate between latently infected and actively diseased individuals. We found that serum levels of the cytokine activin A were associated with increased lung pathology and could discriminate between active tuberculosis and tuberculin skin-test-positive healthy controls. Activin A signals through the ActRIIB receptor, which can be blocked by administration of the ligand trap ActRIIB-Fc, a soluble activin type IIB receptor fused to human IgG1 Fc. In a murine model of tuberculosis, we found that ActRIIB-Fc treatment reduced mycobacterial loads. Strikingly, ActRIIB-Fc treatment significantly increased the number of tissue-resident memory T cells. These results suggest a role for ActRIIB signaling pathways in host responses to and activin A as a biomarker of ongoing disease.
Topics: Humans; Mice; Animals; Mycobacterium tuberculosis; Ligands; Tuberculin; Activins; Tuberculosis; Immunoglobulin G; Biomarkers; Pneumonia; Sarcoidosis
PubMed: 38376260
DOI: 10.1128/mbio.03408-23 -
Biomolecules Jan 2024Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disorder characterized by episodic yet cumulative heterotopic ossification (HO) of skeletal muscles,... (Review)
Review
Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disorder characterized by episodic yet cumulative heterotopic ossification (HO) of skeletal muscles, tendons, ligaments, and fascia. FOP arises from missense mutations in Activin Receptor type I (ACVR1), a type I bone morphogenetic protein (BMP) receptor. Although initial findings implicated constitutive activity of FOP-variant ACVR1 (ACVR1) and/or hyperactivation by BMPs, it was later shown that HO in FOP requires activation of ACVR1 by Activin A. Inhibition of Activin A completely prevents HO in FOP mice, indicating that Activin A is an obligate driver of HO in FOP, and excluding a key role for BMPs in this process. This discovery led to the clinical development of garetosmab, an investigational antibody that blocks Activin A. In a phase 2 trial, garetosmab inhibited new heterotopic bone lesion formation in FOP patients. In contrast, antibodies to ACVR1 activate ACVR1 and promote HO in FOP mice. Beyond their potential clinical relevance, these findings have enhanced our understanding of FOP's pathophysiology, leading to the identification of fibroadipogenic progenitors as the cells that form HO, and the discovery of non-signaling complexes between Activin A and wild type ACVR1 and their role in tempering HO, and are also starting to inform biological processes beyond FOP.
Topics: Humans; Animals; Mice; Myositis Ossificans; Activins; Antibodies, Monoclonal; Bone Morphogenetic Protein Receptors, Type I
PubMed: 38254701
DOI: 10.3390/biom14010101 -
Andrology Jul 2024The activins (A and B) and their binding protein, follistatin, play crucial roles in development, immunoregulation and inflammation throughout the body. In the male... (Review)
Review
The activins (A and B) and their binding protein, follistatin, play crucial roles in development, immunoregulation and inflammation throughout the body. In the male reproductive tract of the mouse, activin A and B production is largely confined to the initial segment and proximal caput of the epididymis and the efferent ducts, under normal conditions, with very low expression in the corpus, cauda and vas deferens. However, activin A protein is present throughout the epididymis and vas deferens and is largely associated with the epithelium and interstitial macrophages. Conversely, the activin-binding protein follistatin is produced in the distal epididymis, with very high expression in the vas deferens. Activin activity in the distal tract is inhibited by follistatin, and the activin-follistatin balance is important for regulating coiling of the duct during epididymal development. In further experiments, as described in this report, in situ hybridisation was used to localise activin A mRNA principally to cells in the periductal zone and interstitium in the efferent ducts and proximal caput. Activin B mRNA, on the other hand, was localised to periductal cells in the efferent ducts and proximal epididymis and, most notably, to epithelial cells in the initial segment. Activin A is implicated in the regulation of mononuclear phagocyte function and immune responses in the caput and stimulates the expression of the key immunoregulatory protein, indoleamine 2,3-dioxygenase in this region. Activin A production in the corpus and cauda increases dramatically during bacterial epididymitis in mice, promoting inflammation and fibrosis and causing damage to the epithelium and obstruction of the epididymal duct. Consequently, it appears that the activin-follistatin axis is crucial for maintaining normal epididymal structure and function, but disruption of this balance during inflammation has deleterious effects on male fertility. Follistatin has therapeutic potential in ameliorating the proinflammatory and profibrotic effects of activins.
Topics: Male; Epididymis; Animals; Activins; Mice; Follistatin; Epididymitis; Humans
PubMed: 37644728
DOI: 10.1111/andr.13523 -
Current Opinion in Supportive and... Dec 2018Anaemia is a common haematological presentation in patients with bone marrow failure, yet a challenging condition to treat. As anaemia has a direct impact on the... (Review)
Review
PURPOSE OF REVIEW
Anaemia is a common haematological presentation in patients with bone marrow failure, yet a challenging condition to treat. As anaemia has a direct impact on the patient's symptoms, managing anaemia in the common bone marrow failure conditions, such as myelodysplastic syndrome will help to improve the quality of life. This review discusses the available treatment options and the benefit of improving the haemoglobin level.
RECENT FINDINGS
Managing anaemia effectively has shown to improve the patient outcome, yet treatment option remain limited. Recently, activin inhibitors such as Luspatercept have shown to be effective in patients' refractory to ESAs and further clinical trials are ongoing to explore this further.
SUMMARY
Transfusion still remains the mainstay of treatment in patients not suitable, lost response or refractory to erythropoiesis-stimulating agents (ESAs). Majority of these patients are not suitable for definite treatment options such as bone marrow transplantation. The aim of treatment remains improving the quality of life and newer therapeutic options may offer better and more sustained response.
Topics: Activin Receptors, Type II; Activins; Anemia; Anemia, Aplastic; Blood Transfusion; Bone Marrow Diseases; Bone Marrow Failure Disorders; Hematinics; Hemoglobinuria, Paroxysmal; Humans; Immunoglobulin Fc Fragments; Quality of Life; Recombinant Fusion Proteins
PubMed: 30299326
DOI: 10.1097/SPC.0000000000000397