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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 Endocrinology 2022The long-standing knowledge that Sertoli cells determine fetal testosterone production levels is not widespread, despite being first reported over a decade ago in... (Review)
Review
The long-standing knowledge that Sertoli cells determine fetal testosterone production levels is not widespread, despite being first reported over a decade ago in studies of mice. Hence any ongoing use of testosterone as a marker of Leydig cell function in fetal testes is inappropriate. By interrogating new scRNAseq data from human fetal testes, we demonstrate this situation is also likely to be true in humans. This has implications for understanding how disruptions to either or both Leydig and Sertoli cells during the masculinization programming window may contribute to the increasing incidence of hypospadias, cryptorchidism, testicular germ cell tumours and adult infertility. We recently discovered that activin A levels directly govern androgen production in mouse Sertoli cells, because the enzymes that drive the conversion of the precursor androgen androstenedione to generate testosterone are produced exclusively in Sertoli cells in response to activin A. This minireview addresses the implications of this growing understanding of how exposures affect fetal masculinization for future research on reproductive health, including during programming windows that may ultimately be relevant for organ development in males and females.
Topics: Activins; Androgens; Animals; Humans; Male; Mice; Sertoli Cells; Testis; Testosterone
PubMed: 35685219
DOI: 10.3389/fendo.2022.898876 -
Endocrinology Jul 2021FSH is critical for fertility. Transcription of FSHB, the gene encoding the beta subunit, is rate-limiting in FSH production and is regulated by both GnRH and activin....
FSH is critical for fertility. Transcription of FSHB, the gene encoding the beta subunit, is rate-limiting in FSH production and is regulated by both GnRH and activin. Activin signals through SMAD transcription factors. Although the mechanisms and importance of activin signaling in mouse Fshb transcription are well-established, activin regulation of human FSHB is less well understood. We previously reported a novel enhancer of FSHB that contains a fertility-associated single nucleotide polymorphism (rs10031006) and requires a region resembling a full (8 base-pair) SMAD binding element (SBE). Here, we investigated the role of the putative SBE within the enhancer in activin and GnRH regulation of FSHB. In mouse gonadotrope-derived LβT2 cells, the upstream enhancer potentiated activin induction of both the human and mouse FSHB proximal promoters and conferred activin responsiveness to a minimal promoter. Activin induction of the enhancer required the SBE and was blocked by the inhibitory SMAD7, confirming involvement of the classical SMAD signaling pathway. GnRH induction of FSHB was also potentiated by the enhancer and dependent on the SBE, consistent with known activin/GnRH synergy regulating FSHB transcription. In DNA pull-down, the enhancer SBE bound SMAD4, and chromatin immunoprecipitation demonstrated SMAD4 enrichment at the enhancer in native chromatin. Combined activin/GnRH treatment elevated levels of the active transcriptional histone marker, histone 3 lysine 27 acetylation, at the enhancer. Overall, this study indicates that the enhancer is directly targeted by activin signaling and identifies a novel, evolutionarily conserved mechanism by which activin and GnRH can regulate FSHB transcription.
Topics: Activins; Animals; Drug Synergism; Enhancer Elements, Genetic; Follicle Stimulating Hormone, beta Subunit; Follistatin; Gonadotropin-Releasing Hormone; Humans; Mice; Promoter Regions, Genetic; Signal Transduction; Smad Proteins; Smad4 Protein; Transcription, Genetic
PubMed: 33824966
DOI: 10.1210/endocr/bqab069 -
The European Respiratory Journal Nov 2023
Topics: Humans; Pulmonary Arterial Hypertension; Activins; Familial Primary Pulmonary Hypertension; Hypertension, Pulmonary
PubMed: 37918877
DOI: 10.1183/13993003.01726-2023 -
Cold Spring Harbor Perspectives in... Jul 2016Since their original discovery as regulators of follicle-stimulating hormone (FSH) secretion and erythropoiesis, the TGF-β family members activin and inhibin have been... (Review)
Review
Since their original discovery as regulators of follicle-stimulating hormone (FSH) secretion and erythropoiesis, the TGF-β family members activin and inhibin have been shown to participate in a variety of biological processes, from the earliest stages of embryonic development to highly specialized functions in terminally differentiated cells and tissues. Herein, we present the history, structures, signaling mechanisms, regulation, and biological processes in which activins and inhibins participate, including several recently discovered biological activities and functional antagonists. The potential therapeutic relevance of these advances is also discussed.
Topics: Activins; Animals; Female; Humans; Inhibins; Ligands; Protein Conformation; Signal Transduction
PubMed: 27328872
DOI: 10.1101/cshperspect.a021881 -
Ginekologia Polska 2016The aim of the study was to evaluate activin A and NGAL levels as potential early markers of perinatal hypoxia.
OBJECTIVES
The aim of the study was to evaluate activin A and NGAL levels as potential early markers of perinatal hypoxia.
MATERIAL AND METHODS
We prospectively studied 58 full-term newborns: 24 with perinatal hypoxia (study group) and 34 healthy controls. Umbilical cord blood samples were obtained from all subjects immediately after delivery for the measurement of activin A and NGAL levels. Both biomarkers were correlated with biochemical indicators od hypoxia and neonatal complications.
RESULTS
Activin A levels were significantly higher in hypoxic as compared to non-hypoxic newborns (0.51 vs. 0.22pg/mL; p<0.01). NGAL levels were also higher in asphyxiated babies as compared to controls (99.1 vs. 22.3ng/mL; p<0.001). A correlation between NGAL and activin A levels was detected (R=0.54; p<0.01). NGAL concentration was also correlated with Apgar score at 5 min. and pH value, HCO3, based deficit and lactate levels. ROC curve analysis demonstrated the cutoff value of >33.9ng/ml for NGAL in prediction of perinatal asphyxia in neonates, with a sensitivity of 100% and specificity 78.3%, whereas the cutoff value for activin A was 0.208ng/ml had, with a sensitivity of 93.1% and only 26.7% specificity.
CONCLUSIONS
Asphyxiated neonates demonstrate elevated NGAL and activin A levels as compared to controls. The correlation of NGAL with clinical and biochemical signs of neonatal hypoxia, as well as higher sensitivity and specificity for NGAL measurements, have led us to believe that NGAL could be a better marker of perinatal hypoxia than activin A.
Topics: Activins; Asphyxia Neonatorum; Biomarkers; Case-Control Studies; Fetal Blood; Humans; Infant, Newborn; Lipocalin-2; Prospective Studies
PubMed: 27306129
DOI: 10.17772/gp/60552 -
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 -
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 -
Endocrinology Dec 2021Endometriosis is characterized by inflammation and fibrotic changes. Our previous study using a mouse model showed that proinflammatory factors present in peritoneal...
Endometriosis is characterized by inflammation and fibrotic changes. Our previous study using a mouse model showed that proinflammatory factors present in peritoneal hemorrhage exacerbated inflammation in endometriosis-like grafts, at least in part through the activation of prostaglandin (PG) E2 receptor and protease-activated receptor (PAR). In addition, menstruation-related factors, PGE2 and thrombin (P/T), a PAR1 agonist induced epithelial-mesenchymal transition (EMT) of endometrial cells under hypoxia. However, the molecular mechanisms by which P/T induce development of endometriosis have not been fully characterized. To investigate the effects of P/T, RNA extracted from endometrial stromal cells (ESCs) treated with P/T were subjected to RNA sequence analysis, and identified activin A, FOS, and GATA2 as upregulated genes. Activin A increased the expression of connective tissue growth factor (CTGF) and mesenchymal marker genes in ESCs. CTGF induced the expression of fibrosis marker type I collagen, fibronectin, and α-smooth muscle actin (αSMA), indicating fibroblast to myofibroblast transdifferentiation (FMT) of ESCs. In addition, activin A, FOS, GATA2, CTGF, and αSMA were localized in endometriosis lesions. Taken together, our data show that P/T induces changes resembling EMT and FMT in ectopic ESCs derived from retrograde menstruation, and that these are associated with fibrotic changes in the lesions. Pharmacological means that block P/T-induced activin A and CTGF signaling may be strategies to inhibit fibrosis in endometriotic lesions.
Topics: Activins; Adult; Cell Transdifferentiation; Cells, Cultured; Connective Tissue Growth Factor; Dinoprostone; Endometriosis; Endometrium; Female; Humans; Myofibroblasts; Peritoneal Diseases; Signal Transduction; Stromal Cells; Thrombin
PubMed: 34606582
DOI: 10.1210/endocr/bqab207 -
Molecular and Cellular Endocrinology Nov 2015Activins are members of the transforming growth factor β superfamily that play an important role in controlling cell proliferation and differentiation in many organs... (Review)
Review
Activins are members of the transforming growth factor β superfamily that play an important role in controlling cell proliferation and differentiation in many organs including the ovary. It is essential that activin signalling be tightly regulated as imbalances can lead to uncontrolled cell proliferation and cancer. This review describes the expression and function of the activins and their known antagonists in both normal and cancerous human ovaries.
Topics: Activins; Cell Line, Tumor; Cell Proliferation; Female; Gene Expression Regulation, Neoplastic; Humans; Inhibins; Ovarian Neoplasms; Ovary; Signal Transduction
PubMed: 26277402
DOI: 10.1016/j.mce.2015.08.011