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Placenta May 2023Activin A is a two-subunit protein belonging to the transforming growth factor β superfamily. First discovered almost three decades ago, it has since been implicated in... (Review)
Review
Activin A is a two-subunit protein belonging to the transforming growth factor β superfamily. First discovered almost three decades ago, it has since been implicated in diverse physiological roles, ranging from wound repair to reproduction. After 30 years of research, altered activin A levels are now understood to be associated with the development of various diseases, making activin A a potential therapeutic target. In pregnancy, the placenta and fetal membranes are major producers of activin A, with significantly enhanced serum concentrations now recognised as a contributor to numerous gestational disorders. Evidence now suggests that circulating levels of activin A may be clinically relevant in the early detection of pregnancy complications, including miscarriage and preeclampsia. This review aims to summarise our current understanding of activin A as a potential diagnostic marker in common pregnancy pathologies.
Topics: Pregnancy; Female; Humans; Inhibins; Activins; Reproduction; Pregnancy Complications
PubMed: 37028223
DOI: 10.1016/j.placenta.2023.03.008 -
Physiological Reviews Jan 2019Activins are dimeric glycoproteins belonging to the transforming growth factor beta superfamily and resulting from the assembly of two beta subunits, which may also be... (Review)
Review
Activins are dimeric glycoproteins belonging to the transforming growth factor beta superfamily and resulting from the assembly of two beta subunits, which may also be combined with alpha subunits to form inhibins. Activins were discovered in 1986 following the isolation of inhibins from porcine follicular fluid, and were characterized as ovarian hormones that stimulate follicle stimulating hormone (FSH) release by the pituitary gland. In particular, activin A was shown to be the isoform of greater physiological importance in humans. The current understanding of activin A surpasses the reproductive system and allows its classification as a hormone, a growth factor, and a cytokine. In more than 30 yr of intense research, activin A was localized in female and male reproductive organs but also in other organs and systems as diverse as the brain, liver, lung, bone, and gut. Moreover, its roles include embryonic differentiation, trophoblast invasion of the uterine wall in early pregnancy, and fetal/neonate brain protection in hypoxic conditions. It is now recognized that activin A overexpression may be either cytostatic or mitogenic, depending on the cell type, with important implications for tumor biology. Activin A also regulates bone formation and regeneration, enhances joint inflammation in rheumatoid arthritis, and triggers pathogenic mechanisms in the respiratory system. In this 30-yr review, we analyze the evidence for physiological roles of activin A and the potential use of activin agonists and antagonists as therapeutic agents.
Topics: Activins; Animals; Follicle Stimulating Hormone; Glycoproteins; Humans; Inhibins; Mammals; Reproduction
PubMed: 30540228
DOI: 10.1152/physrev.00002.2018 -
Oncoimmunology Feb 2021The mechanisms accountable for the infiltration of regulatory T cells into an irradiated tumor remain elusive. In our recent study, we demonstrate that activin A... (Review)
Review
The mechanisms accountable for the infiltration of regulatory T cells into an irradiated tumor remain elusive. In our recent study, we demonstrate that activin A promotes regulatory T cells in tumors, and impairs anti-tumor immune responses induced by radiotherapy and TGF-β blockade. Dual blockade of activin A and TGF-β may be necessary to reduce regulatory T cells mediated immunosuppression driven by radiation therapy.
Topics: Activins; Immune Tolerance; T-Lymphocytes, Regulatory
PubMed: 33628624
DOI: 10.1080/2162402X.2021.1883288 -
Frontiers in Immunology 2022Activin A, a critical member of the transforming growth factor-β (TGF-β) superfamily, is a pluripotent factor involved in allergies, autoimmune diseases, cancers and... (Review)
Review
Activin A, a critical member of the transforming growth factor-β (TGF-β) superfamily, is a pluripotent factor involved in allergies, autoimmune diseases, cancers and other diseases with immune disorder. Similar to its family member, TGF-β, activin A also transmits signals through SMAD2/SMAD3, however, they bind to distinct receptors. Recent studies have uncovered that activin A plays a pivotal role in both innate and adaptive immune systems. Here we mainly focus its effects on activation, differentiation, proliferation and function of cells which are indispensable in the immune system and meanwhile make some comparisons with those of TGF-β.
Topics: Activins; Signal Transduction; Trans-Activators; Transforming Growth Factor beta
PubMed: 35774793
DOI: 10.3389/fimmu.2022.921366 -
Development (Cambridge, England) Feb 2015Activin/Nodal growth factors control a broad range of biological processes, including early cell fate decisions, organogenesis and adult tissue homeostasis. Here, we... (Review)
Review
Activin/Nodal growth factors control a broad range of biological processes, including early cell fate decisions, organogenesis and adult tissue homeostasis. Here, we provide an overview of the mechanisms by which the Activin/Nodal signalling pathway governs stem cell function in these different stages of development. We describe recent findings that associate Activin/Nodal signalling to pathological conditions, focusing on cancer stem cells in tumorigenesis and its potential as a target for therapies. Moreover, we will discuss future directions and questions that currently remain unanswered on the role of Activin/Nodal signalling in stem cell self-renewal, differentiation and proliferation.
Topics: Activins; Animals; Cell Differentiation; Humans; Nodal Protein; Pluripotent Stem Cells; Signal Transduction; Stem Cells
PubMed: 25670788
DOI: 10.1242/dev.091769 -
Bioscience Reports Aug 2019Heterotopic ossification (HO) is the aberrant formation of mature, lamellar bone in nonosseous tissue. Fibrodysplasia ossificans progressiva (FOP) is a rare and... (Review)
Review
Heterotopic ossification (HO) is the aberrant formation of mature, lamellar bone in nonosseous tissue. Fibrodysplasia ossificans progressiva (FOP) is a rare and devastating genetic disorder that causes progressive HO in the ligaments, tendons, and muscles throughout the body. FOP is attributed to an autosomal mutation in activin receptor-like kinase 2 (ALK2), a bone morphogenetic protein (BMP) type I receptor. Initial studies show that mutant ALK2 drives HO by constitutively activating the BMP signaling pathway. Recently, mutant ALK2 has been shown to transduce Smad1/5 signaling and enhance chondrogenesis, calcification in response to Activin A, which normally signals through Smad2/3 and inhibits BMP signaling pathway. Furthermore, Activin A induces heterotopic bone formation via mutant ALK2, while inhibition of Activin A blocks spontaneous and trauma-induced HO. In this manuscript, we describe the molecular mechanism of the causative gene in FOP, mainly focusing on the prominent role of Activin A in HO. It reveals a potential strategy for prevention and treatment of FOP by inhibition of Activin A. Further studies are needed to explore the cellular and molecular mechanisms of Activin A in FOP in more detail.
Topics: Activins; Animals; Humans; Myositis Ossificans; Ossification, Heterotopic; Signal Transduction
PubMed: 31341010
DOI: 10.1042/BSR20190377 -
Circulation Jun 2023Activins are novel therapeutic targets in pulmonary arterial hypertension (PAH). We therefore studied whether key members of the activin pathway could be used as PAH...
BACKGROUND
Activins are novel therapeutic targets in pulmonary arterial hypertension (PAH). We therefore studied whether key members of the activin pathway could be used as PAH biomarkers.
METHODS
Serum levels of activin A, activin B, α-subunit of inhibin A and B proteins, and the antagonists follistatin and follistatin-like 3 (FSTL3) were measured in controls and in patients with newly diagnosed idiopathic, heritable, or anorexigen-associated PAH (n=80) at baseline and 3 to 4 months after treatment initiation. The primary outcome was death or lung transplantation. Expression patterns of the inhibin subunits, follistatin, FSTL3, Bambi, Cripto, and the activin receptors type I (ALK), type II (ACTRII), and betaglycan were analyzed in PAH and control lung tissues.
RESULTS
Death or lung transplantation occurred in 26 of 80 patients (32.5%) over a median follow-up of 69 (interquartile range, 50-81) months. Both baseline (hazard ratio, 1.001 [95% CI, 1.000-1.001]; =0.037 and 1.263 [95% CI, 1.049-1.520]; =0.014, respectively) and follow-up (hazard ratio, 1.003 [95% CI, 1.001-1.005]; =0.001 and 1.365 [95% CI, 1.185-1.573]; <0.001, respectively) serum levels of activin A and FSTL3 were associated with transplant-free survival in a model adjusted for age and sex. Thresholds determined by receiver operating characteristic analyses were 393 pg/mL for activin A and 16.6 ng/mL for FSTL3. When adjusted with New York Heart Association functional class, 6-minute walk distance, and N-terminal pro-B-type natriuretic peptide, the hazard ratios for transplant-free survival for baseline activin A <393 pg/mL and FSTL3 <16.6 ng/mL were, respectively, 0.14 (95% CI, 0.03-0.61; =0.009) and 0.17 (95% CI, 0.06-0.45; <0.001), and for follow-up measures, 0.23 (95% CI, 0.07-0.78; =0.019) and 0.27 (95% CI, 0.09-0.78, =0.015), respectively. Prognostic values of activin A and FSTL3 were confirmed in an independent external validation cohort. Histological analyses showed a nuclear accumulation of the phosphorylated form of Smad2/3, higher immunoreactivities for ACTRIIB, ALK2, ALK4, ALK5, ALK7, Cripto, and FSTL3 in vascular endothelial and smooth muscle layers, and lower immunostaining for inhibin-α and follistatin.
CONCLUSIONS
These findings offer new insights into the activin signaling system in PAH and show that activin A and FSTL3 are prognostic biomarkers for PAH.
Topics: Humans; Follistatin; Pulmonary Arterial Hypertension; Inhibins; Activins; Lung
PubMed: 37096577
DOI: 10.1161/CIRCULATIONAHA.122.061501 -
Current Opinion in Nephrology and... Sep 2018Sotatercept and luspatercept are recombinant soluble activin type-II receptor-IgG-Fc fusion proteins that are tested in clinical trials for the treatment of various... (Review)
Review
PURPOSE OF REVIEW
Sotatercept and luspatercept are recombinant soluble activin type-II receptor-IgG-Fc fusion proteins that are tested in clinical trials for the treatment of various types of anemias, including renal anemia. The mechanism of the action of the novel drugs is incompletely understood, but it seems to be based on the inactivation of soluble proteins of the transforming growth factor-ß (TGFß) family. This review considers pros and cons of the clinical use of the drugs in reference to the current therapy with recombinant erythropoiesis-stimulating agents (ESAs).
RECENT FINDINGS
One or more activin type-II receptor (ActRII) ligands appear to inhibit erythroid precursors, for example growth and differentiation factor 11. Trapping of these ligands by the recombinant ActRII fusion proteins, sotatercept and luspatercept increases red blood cell numbers and hemoglobin levels in humans. Reportedly, the novel compounds were well tolerated in trials on healthy volunteers and patients suffering from anemia due to chronic kidney disease or malignancies. On approval, the drugs may prove particularly useful in patients suffering from ineffective erythropoiesis, such as in myelodysplastic syndrome, multiple myeloma or ß-thalassemia, where ESAs are of little use. Independent of their effect on erythropoiesis, ActRII ligand traps were found to exert beneficial effects on renal tissue in experimental animals.
SUMMARY
ESAs are likely to remain standard of care in renal anemia. There is a need for a better understanding of the effects of ActRII ligand traps on TGFß-like proteins. The novel drugs have not been approved for sale as therapeutics so far. Their long-term efficacy and safety still needs to be proven, particularly with respect to immunogenicity. Antifibrotic effects may be worthy to be investigated in humans.
Topics: Activin Receptors; Activin Receptors, Type II; Activins; Anemia; Animals; Erythropoiesis; Hematinics; Humans; Immunoglobulin Fc Fragments; Ligands; Recombinant Fusion Proteins; Renal Insufficiency, Chronic; Transforming Growth Factor beta
PubMed: 29847322
DOI: 10.1097/MNH.0000000000000433 -
Cytokine Sep 2020Activins and inhibins - comprising activin A, B, AB, C and E, and inhibin A and B isoforms - belong to the transforming growth factor beta (TGFβ) superfamily. They... (Review)
Review
Activins and inhibins - comprising activin A, B, AB, C and E, and inhibin A and B isoforms - belong to the transforming growth factor beta (TGFβ) superfamily. They regulate several biological processes, including cellular proliferation, differentiation and invasiveness, to enhance the formation and functioning of many human tissues and organs. In this review, we have discussed the role of activin and inhibin signaling in the physiological and female-specific pathological events that occur in the female reproductive system. The up-to-date evidence indicates that these cytokines regulate germ cell development, follicular development, ovulation, uterine receptivity, decidualization and placentation through the activation of several signaling pathways; and that their dysregulated expression is involved in the pathogenesis and pathophysiology of the numerous diseases, including pregnancy complications, that disturb reproduction. Hence, some of the isoforms have been suggested as potential biomarkers and therapeutic targets for the management of some of these diseases. Tackling the research directions highlighted in this review will enhance a detailed comprehension and the clinical utility of these cytokines.
Topics: Activins; Animals; Female; Humans; Inhibins; Pregnancy; Reproduction; Signal Transduction
PubMed: 32438278
DOI: 10.1016/j.cyto.2020.155105 -
Vitamins and Hormones 2011Activins, members of the TGF-β family, are multifunctional growth and differentiation factors. Activins regulate glucose/energy metabolism by promoting the... (Review)
Review
Activins, members of the TGF-β family, are multifunctional growth and differentiation factors. Activins regulate glucose/energy metabolism by promoting the differentiation of insulin-producing and -responsive cells, and regulating function of the differentiated cells. In the pancreas, activins stimulate the differentiation of β cells and secretion of insulin, which enables the cells to respond to glucose uptake efficiently. By contrast, in the liver, skeletal muscle and white adipose tissue, activins exert negative regulation on organogenesis, which leads to impaired insulin sensitivity. Activins induce the phenotypic switch of macrophages from the M1 to M2 phenotypes, which reduces inflammation. Since adipose inflammation is closely associated with insulin resistance and the onset of type 2 diabetes, activins may improve insulin resistance through their anti-inflammatory activity. Because activins modulate events involved in insulin sensitivity in a tissue-dependent manner, the activities of activins should be locally regulated to improve whole-body insulin responsiveness. Thus, activins or activin inhibitors may be effective as therapeutic agents for metabolic syndrome.
Topics: Activins; Animals; Energy Metabolism; Glucose; Humans; Insulin
PubMed: 21353883
DOI: 10.1016/B978-0-12-385961-7.00011-1