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1
Klotz, B., L. Seefried, R. Ebert, and F. Jakob. "Activin-Antagonisten in der Therapie der Osteoporose." Osteologie 20, no. 03 (2011): 217–21. http://dx.doi.org/10.1055/s-0037-1619996.
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ZusammenfassungActivin A ist ein Polypeptid mit vielfältigen biologischen Wirkungen auf die Regulation der Fertilität, die Pluripotenz und Differenzierung von Stammzellen, die Differenzierung von Neuronen, Inselzellen und Immunzellen und die Regulation des Stoffwechsels. Activin gehört zu den Liganden der Familie der TGFβ- Superfamilie. Die Activine A, B und C binden an die Typ-II-BMP-Rezeptoren (Activin-Rezeptor IIA [ActRIIA] und IIB [ActRIIB]) und rekrutieren spezifische Typ-I-Rezeptoren (activin receptor-like kinase 2 [ALK2], 4 [ALK4] und 7 ]ALK7]). Da der ActRIIB auch andere Faktoren wie z. B. Myostatin (GDF8) und die Bone Morphogenetic Proteins 7 und 2 (BMP-7, BMP-2) bindet, konkurrieren diese Liganden um den Rezeptor. Im Alter findet man erhöhte Activin- Spiegel im Serum. Activin-Antagonisten verändern die Balance zwischen den verschiedenen Liganden und verursachen eine veränderte Genregulation an allen Zellen, die entsprechende Signalsysteme exprimieren. Ein ACTIIIGG- Fusionsprotein mit Activin-antagonistischer Wirkung wird unter dem Namen Sotatercept (ACE-011) bereits klinisch als Medikament gegen die Tumor-induzierte und die Chemotherapie- induzierte Anämie erprobt und präklinisch für die Therapie der Osteoporose entwickelt. Am Knochen entfaltet der Antagonist eine duale Wirkung, er zeigt ausgeprägte anabole Effekte und verringert die Knochenresorption. In einem Mausmodell der Androgendefizienz werden zudem eine anabole Wirkung am Muskel und eine Verringerung des Fettgewebes beschrieben. Weitere Studien sind auf dem Weg, um sicherzustellen, dass das vielversprechende Medikament bei der Anwendung am Menschen neben der Effizienz auch ein gutes Sicherheits- und Nebenwirkungsprofil besitzt. Wenn es die Klinikreife erreicht, wird es unser therapeutisches Arsenal zur Behandlung der Osteoporose und möglicherweise auch der Sarkopenie wesentlich bereichern.
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Olsen, Oddrun Elise, Hanne Hella, Samah Elsaadi, Carsten Jacobi, Erik Martinez-Hackert, and Toril Holien. "Activins as Dual Specificity TGF-β Family Molecules: SMAD-Activation via Activin- and BMP-Type 1 Receptors." Biomolecules 10, no. 4 (March 29, 2020): 519. http://dx.doi.org/10.3390/biom10040519.
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Activins belong to the transforming growth factor (TGF)-β family of multifunctional cytokines and signal via the activin receptors ALK4 or ALK7 to activate the SMAD2/3 pathway. In some cases, activins also signal via the bone morphogenetic protein (BMP) receptor ALK2, causing activation of the SMAD1/5/8 pathway. In this study, we aimed to dissect how activin A and activin B homodimers, and activin AB and AC heterodimers activate the two main SMAD branches. We compared the activin-induced signaling dynamics of ALK4/7-SMAD2/3 and ALK2-SMAD1/5 in a multiple myeloma cell line. Signaling via the ALK2-SMAD1/5 pathway exhibited greater differences between ligands than signaling via ALK4/ALK7-SMAD2/3. Interestingly, activin B and activin AB very potently activated SMAD1/5, resembling the activation commonly seen with BMPs. As SMAD1/5 was also activated by activins in other cell types, we propose that dual specificity is a general mechanism for activin ligands. In addition, we found that the antagonist follistatin inhibited signaling by all the tested activins, whereas the antagonist cerberus specifically inhibited activin B. Taken together, we propose that activins may be considered dual specificity TGF-β family members, critically affecting how activins may be considered and targeted clinically.
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Schneyer, Alan, Amy Schoen, Alicia Quigg, and Yisrael Sidis. "Differential Binding and Neutralization of Activins A and B by Follistatin and Follistatin Like-3 (FSTL-3/FSRP/FLRG)." Endocrinology 144, no. 5 (May 1, 2003): 1671–74. http://dx.doi.org/10.1210/en.2002-0203.
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Modulation of activin and other TGFβ superfamily signaling is the primary mechanism of action for both follistatin (FS) and FS-like 3 (FSTL-3). However, most studies of these ligands use activin A due to its wide availability. We have now tested the ability of FS288 and FSTL-3 to bind and neutralize activin B relative to activin A. Activin B bound to both FS and FSTL-3 at a potency approximately 10-fold lower than that of activin A. Moreover, whereas both activins had similar biological activity in 293 cell reporter assays, FS and FSTL-3 were approximately 3-fold more effective in neutralizing activin A relative to activin B. These results suggest that neutralization of activins A and B by FS and FSTL-3 are not identical, so that the relative activity of each activin in tissues where both are produced, such as in the ovary, could be quite different. In addition, biological systems that use primarily activin B, but which have been examined in vitro using activin A, may need to be reevaluated to determine the actual physiologic roles of FS or FSTL-3.
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Vänttinen, Teemu, Tiina Kuulasmaa, Jianqi Liu, and Raimo Voutilainen. "Expression of Activin/Inhibin Receptor and Binding Protein Genes and Regulation of Activin/Inhibin Peptide Secretion in Human Adrenocortical Cells." Journal of Clinical Endocrinology & Metabolism 87, no. 9 (September 1, 2002): 4257–63. http://dx.doi.org/10.1210/jc.2002-020460.
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Activins and inhibins are glycoprotein hormones produced mainly in gonads but also in other organs. They are believed to be important para/autocrine regulators of various cell functions. We investigated activin/inhibin receptor and binding protein gene expression and the regulation of activin/inhibin secretion in human adrenal cells. RT-PCR revealed inhibin/activin α-, βA/B-subunit, follistatin, activin type I/II receptor, and inhibin receptor (betaglycan and inhibin-binding protein) mRNA expression in fetal and adult adrenals and cultured adrenocortical cells. Cultured cells secreted activin A and inhibin A/B as determined by specific ELISAs. ACTH stimulated inhibin A/B secretion in fetal (1.8- and 1.8-fold of control, respectively) and in adult cells (3.4- and 1.7-fold of control, respectively) without significant effect on activin A. 8-bromoadenosine cAMP (protein kinase A activator) increased activin A and inhibin A/B secretion in the human adrenocortical NCI-H295R cell line (32-, 17-, and 3-fold of control, respectively). 12-O-tetradecanoyl phorbol-13-acetate (protein kinase C activator) stimulated both activin A and inhibin A secretion (764- and 32-fold of control, respectively), and activin treatment increased inhibin B secretion in these cells (25-fold of control). In conclusion, human adrenocortical cells produce dimeric activins and inhibins. ACTH stimulates inhibin secretion and decreases activin/inhibin secretion ratio, probably via the protein kinase A signal transduction pathway. This, together with the adrenocortical activin/ inhibin receptor and binding protein expression, suggests a physiological role for activins and inhibins in the human adrenal gland.
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Merino, R., D. Macias, Y. Ganan, J. Rodriguez-Leon, A. N. Economides, C. Rodriguez-Esteban, J. C. Izpisua-Belmonte, and J. M. Hurle. "Control of digit formation by activin signalling." Development 126, no. 10 (May 15, 1999): 2161–70. http://dx.doi.org/10.1242/dev.126.10.2161.
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Major advances in the genetics of vertebrate limb development have been obtained in recent years. However, the nature of the signals which trigger differentiation of the mesoderm to form the limb skeleton remains elusive. Previously, we have obtained evidence for a role of TGFbeta2 in digit formation. Here, we show that activins A and B and/or AB are also signals involved in digit skeletogenesis. activin betaA gene expression correlates with the initiation of digit chondrogenesis while activin betaB is expressed coincidently with the formation of the last phalanx of each digit. Exogenous administration of activins A, B or AB into the interdigital regions induces the formation of extra digits. follistatin, a natural antagonist of activins, is expressed, under the control of activin, peripherally to the digit chondrogenic aggregates marking the prospective tendinous blastemas. Exogenous application of follistatin blocks physiological and activin-induced digit formation. Evidence for a close interaction between activins and other signalling molecules, such as BMPs and FGFs, operating at the distal tip of the limb at these stages is also provided. Chondrogenesis by activins is mediated by BMPs through the regulation of the BMP receptor bmpR-1b and in turn activin expression is upregulated by BMP signalling. In addition, AER hyperactivity secondary to Wnt3A misexpression or local administration of FGFs, inhibits activin expression. In correlation with the restricted expression of activins in the course of digit formation, neither activin nor follistatin treatment affects the development of the skeletal components of the stylopod or zeugopod indicating that the formation of the limb skeleton is regulated by segment-specific chondrogenic signals.
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Young, J. M., S. Henderson, C. Souza, H. Ludlow, N. Groome, and A. S. McNeilly. "Activin B is produced early in antral follicular development and suppresses thecal androgen production." REPRODUCTION 143, no. 5 (May 2012): 637–50. http://dx.doi.org/10.1530/rep-11-0327.
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Little is known about the role of activin B during folliculogenesis. This study investigated the expression levels of activin/inhibin subunits (βA, βB, and α), steroid enzyme, and gonadotrophin receptors in theca (TC) and granulosa cells (GC) by QPCR and activin A and B and inhibin A protein levels in follicular fluid (FF) of developing sheep follicles during estrus and anestrus. The effect of activin B on androgen production from primary TC cultures in vitro was also assessed. During folliculogenesis, in anestrus and estrus, FF activin B concentrations and thecal and GC activin βB mRNA levels decreased as follicle diameter increased from 1–3 to >6 mm regardless of estrogenic status. Estrogenic preovulatory follicles had reduced concentrations of FF activins B and A, and TC and GCs expressed higher levels of activin βA mRNA at 3–4 mm, and TCs more inhibin α mRNA at >4 mm stages of development compared with nonestrogenic follicles. Activin B decreased androstenedione production from primary TCs in vitro, an effect blocked by inhibin A. Thus, sheep follicles 1–3 mm in diameter contained high FF levels of activin B, which decreased as the follicle size increased, and, like activin A, suppressed thecal androgen production in vitro, an effect blocked by inhibin. Furthermore, the theca of large estrogenic follicles expressed high levels of inhibin α and activin βA mRNA suggesting local thecal derived inhibin A production. This would inhibit the negative effects of thecal activins B and A ensuring maximum androgen production for enhanced estradiol production by the preovulatory follicle(s).
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Wu, Hui, Michael Wu, Yi Chen, Carolyn A. Allan, David J. Phillips, and Mark P. Hedger. "Correlation between Blood Activin Levels and Clinical Parameters of Type 2 Diabetes." Experimental Diabetes Research 2012 (2012): 1–9. http://dx.doi.org/10.1155/2012/410579.
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Aims. Activins A and B, and their binding protein, follistatin, regulate glucose metabolism and inflammation. Consequently, their role in type 2 diabetes (T2D) was examined.Methods. Blood was taken from fasted participants (34 males; 58 females; 50–75 years) with diabetes or during an oral glucose tolerance test (OGTT). Clinical parameters were assessed, and blood assayed for activins, follistatin, and C-reactive protein.Results. Serum levels of activin A (93.3 ± 27.0 pg/mL, mean ± SD), B (81.8 ± 30.8 pg/mL), or follistatin (6.52 ± 3.15 ng/mL) were not different (P>0.05) between subjects with normal OGTT (n=39), impaired glucose tolerance and/or fasting glucose (n=17), or T2D (n=36). However, activin A and/or activin B were positively correlated with parameters of insulin resistance and T2D, including fasting glucose (P<0.001), fasting insulin (P=0.02), glycated hemoglobin (P=0.003), and homeostasis model assessment of insulin resistance (HOMA-IR;P<0.001). Follistatin was positively correlated with HOMA-IR alone (P=0.01).Conclusions. These data indicate that serum measurements of activin A, B, or follistatin cannot discriminate risk for T2D in individual patients, but the activins display a positive relationship with clinical parameters of the disease.
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Albano, R. M., N. Groome, and J. C. Smith. "Activins are expressed in preimplantation mouse embryos and in ES and EC cells and are regulated on their differentiation." Development 117, no. 2 (February 1, 1993): 711–23. http://dx.doi.org/10.1242/dev.117.2.711.
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Members of the activin family have been suggested to act as mesoderm-inducing factors during early amphibian development. Little is known, however, about mesoderm formation in the mammalian embryo, and as one approach to investigating this we have studied activin expression during early mouse development. Activins are homo- or heterodimers of the beta A or beta B subunits of inhibin, itself a heterodimer consisting of one of the beta subunits together with an alpha subunit. Our results indicate that the oocyte contains mRNA encoding all three subunits, and antibody staining demonstrates the presence of both alpha and beta protein chains. From the fertilized egg stage onwards, alpha subunit protein cannot be detected, so the presence of beta subunits reflects the presence of activin rather than inhibin. Maternal levels of activin protein decline during early cleavage stages but increase, presumably due to zygotic transcription (see below), in the compacted morula. By 3.5 days, only the inner cell mass (ICM) cells of the blastocyst express activin, but at 4.5 days the situation is reversed; activin expression is confined to the trophectoderm. Using reverse transcription-PCR, neither beta A nor beta B mRNA was detectable at the two-cell stage but transcripts encoding both subunits were detectable at the morula stage, with beta B mRNA persisting into the blastocyst. We have also analyzed activin and inhibin expression in ES and EC cells. Consistent with the observation that activins are expressed in the ICM of 3.5-day blastocysts, we find high levels of beta A and beta B mRNA in all eight ES cell lines tested. F9 EC cells express only activin beta B, together with low levels of the inhibin alpha chain. When ES and EC cells are induced to differentiate, levels of activin fall dramatically. These results are consistent with a role for activins in mesoderm formation and other steps of early mouse development.
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Andrzejewski, Danielle, Melissa L. Brown, Nathan Ungerleider, Amy Burnside, and Alan L. Schneyer. "Activins A and B Regulate Fate-Determining Gene Expression in Islet Cell Lines and Islet Cells From Male Mice." Endocrinology 156, no. 7 (May 11, 2015): 2440–50. http://dx.doi.org/10.1210/en.2015-1167.
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TGFβ superfamily ligands, receptors, and second messengers, including activins A and B, have been identified in pancreatic islets and proposed to have important roles regulating development, proliferation, and function. We previously demonstrated that Fstl3 (an antagonist of activin activity) null mice have larger islets with β-cell hyperplasia and improved glucose tolerance and insulin sensitivity in the absence of altered β-cell proliferation. This suggested the hypothesis that increased activin signaling influences β-cell expansion by destabilizing the α-cell phenotype and promoting transdifferentiation to β-cells. We tested the first part of this hypothesis by treating α- and β-cell lines and sorted mouse islet cells with activin and related ligands. Treatment of the αTC1-6 α cell line with activins A or B suppressed critical α-cell gene expression, including Arx, glucagon, and MafB while also enhancing β-cell gene expression. In INS-1E β-cells, activin A treatment induced a significant increase in Pax4 (a fate determining β-cell gene) and insulin expression. In sorted primary islet cells, α-cell gene expression was again suppressed by activin treatment in α-cells, whereas Pax4 was enhanced in β-cells. Activin treatment in both cell lines and primary cells resulted in phosphorylated mothers against decapentaplegic-2 phosphorylation. Finally, treatment of αTC1-6 cells with activins A or B significantly inhibited proliferation. These results support the hypothesis that activin signaling destabilized the α-cell phenotype while promoting a β-cell fate. Moreover, these results support a model in which the β-cell expansion observed in Fstl3 null mice may be due, at least in part, to enhanced α- to β-cell transdifferentiation.
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Tang, Pei, Xueer Wang, Min Zhang, Simin Huang, Chuxi Lin, Fang Yan, Ying Deng, Lu Zhang, and Lin Zhang. "Activin B Stimulates Mouse Vibrissae Growth and Regulates Cell Proliferation and Cell Cycle Progression of Hair Matrix Cells through ERK Signaling." International Journal of Molecular Sciences 20, no. 4 (February 15, 2019): 853. http://dx.doi.org/10.3390/ijms20040853.
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Activins and their receptors play important roles in the control of hair follicle morphogenesis, but their role in vibrissae follicle growth remains unclear. To investigate the effect of Activin B on vibrissae follicles, the anagen induction assay and an in vitro vibrissae culture system were constructed. Hematoxylin and eosin staining were performed to determine the hair cycle stages. The 5-ethynyl-2′-deoxyuridine (EdU) and Cell Counting Kit-8 (CCK-8) assays were used to examine the cell proliferation. Flow cytometry was used to detect the cell cycle phase. Inhibitors and Western blot analysis were used to investigate the signaling pathway induced by Activin B. As a result, we found that the vibrissae follicle growth was accelerated by 10 ng/mL Activin B in the anagen induction assay and in an organ culture model. 10 ng/mL Activin B promoted hair matrix cell proliferation in vivo and in vitro. Moreover, Activin B modulates hair matrix cell growth through the ERK–Elk1 signaling pathway, and Activin B accelerates hair matrix cell transition from the G1/G0 phase to the S phase through the ERK–Cyclin D1 signaling pathway. Taken together, these results demonstrated that Activin B may promote mouse vibrissae growth by stimulating hair matrix cell proliferation and cell cycle progression through ERK signaling.
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Synolaki, Evgenia, Vasileios Papadopoulos, Georgios Divolis, Olga Tsahouridou, Efstratios Gavriilidis, Georgia Loli, Ariana Gavriil, et al. "The Activin/Follistatin Axis Is Severely Deregulated in COVID-19 and Independently Associated With In-Hospital Mortality." Journal of Infectious Diseases 223, no. 9 (February 24, 2021): 1544–54. http://dx.doi.org/10.1093/infdis/jiab108.
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Abstract Background Activins are members of the transforming growth factor-β 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.
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Mellor, Sally L., Emma M. A. Ball, Anne E. O’Connor, Jean-François Ethier, Mark Cranfield, Jacqueline F. Schmitt, David J. Phillips, Nigel P. Groome, and Gail P. Risbridger. "Activin βC-Subunit Heterodimers Provide a New Mechanism of Regulating Activin Levels in the Prostate." Endocrinology 144, no. 10 (October 1, 2003): 4410–19. http://dx.doi.org/10.1210/en.2003-0225.
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Activins are formed by dimerization of β-subunits and, as members of the TGF-β superfamily, have diverse roles as potent growth and differentiation factors. As the biological function of the activin C homodimer (βC-βC) is unknown, we sought to compare activin A (βA-βA), B (βB-βB), and C homodimer bioactivities and to investigate the consequences of activin βC-subunit overexpression in prostate tumor cells. Exogenous activin A and B homodimers inhibited cell growth and activated activin-responsive promoters. In contrast, the activin C homodimer was unable to elicit these responses. We previously showed that the activin βC-subunit heterodimerized with activin βAin vitro to form activin AC. Therefore, we hypothesize that the activin βC-subunit regulates the levels of bioactive activin A by the formation of activin AC heterodimers. To test this hypothesis, we measured activin AC heterodimer production using a novel specific two-site ELISA that we developed for this purpose. In the PC3 human prostate tumor cell line, activin βC-subunit overexpression increased activin AC heterodimer levels, concomitantly reduced activin A levels, and decreased activin signaling. Overall, these data are consistent with a role for the activin βC-subunit as a regulatory mechanism to reduce activin A secretion via intracellular heterodimerization.
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Bonomi, Lara, Melissa Brown, Nathan Ungerleider, Meghan Muse, Martin M. Matzuk, and Alan Schneyer. "Activin B regulates islet composition and islet mass but not whole body glucose homeostasis or insulin sensitivity." American Journal of Physiology-Endocrinology and Metabolism 303, no. 5 (September 1, 2012): E587—E596. http://dx.doi.org/10.1152/ajpendo.00177.2012.
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Based on the phenotype of the activin-like kinase-7 (ALK7)-null mouse, activins A and B have been proposed to play distinct roles in regulating pancreatic islet function and glucose homeostasis, with activin A acting to enhance islet function and insulin release while activin B antagonizes these actions. We therefore hypothesized that islets from activin B-null (BBKO) mice would have enhanced glucose-stimulated insulin secretion. In addition, we hypothesized that this enhanced islet function would translate into increased whole body glucose tolerance. We tested these hypotheses by analyzing glucose homeostasis, insulin secretion, and islet function in BBKO mice. No differences were observed in fasting glucose or insulin levels, glucose tolerance, or insulin sensitivity compared with weight-matched young or older males. Similarly, there were no significant differences in insulin secretion comparing islets from WT or BBKO males at either age. However, BBKO islets were more sensitive to activin A, myostatin (MSTN), and follistatin (FST) treatments, so that activin A and FST inhibited and MSTN enhanced glucose stimulated insulin secretion. While mean islet area and the distribution of islet areas were not different between the genotypes, islet mass, islet number, and the proportion of α-cells/islet were significantly reduced in BBKO islets. These results indicate that activin B does not antagonize activin A to influence whole body glucose homeostasis or β-cell function but does influence islet mass and proportion of α-cells/islet. Therefore, loss of activin B signaling alone does not account for the ALK7-null phenotype, but activin B may have important roles in modulating islet mass, islet number, and the cellular composition of islets.
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Wijayarathna, Rukmali, David M. de Kretser, Rajini Sreenivasan, Helen Ludlow, Ralf Middendorff, Andreas Meinhardt, Kate L. Loveland, and Mark P. Hedger. "Comparative analysis of activins A and B in the adult mouse epididymis and vas deferens." Reproduction 155, no. 1 (January 2018): 15–23. http://dx.doi.org/10.1530/rep-17-0485.
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Activin A regulates testicular and epididymal development, but the role of activin B in the epididymis and vas deferens is unknown. Mouse models with reduced activin A (Inhba+/− and InhbaBK/+), or its complete absence (InhbaBK/BK), were investigated to identify specific roles of activins in the male reproductive tract. In 8-week-old Inhba+/− mice, serum activin A decreased by 70%, with a 50% reduction of gene expression and protein in the testis, epididymis and vas deferens. Activin B and the activin-binding protein, follistatin, were similar to wild-type. Testis weights were slightly reduced in Inhba+/− mice, but the epididymis and vas deferens were normal, while the mice were fertile. Activin A was decreased by 70% in the serum, testis, epididymis and vas deferens of InhbaBK/+ mice and was undetectable in InhbaBK/BK mice, but activin B and follistatin levels were similar to wild-type. In 6-week-old InhbaBK/BK mice, testis weights were 60% lower and epididymal weights were 50% lower than in either InhbaBK/+ or wild-type mice. The cauda epididymal epithelium showed infoldings and less intra-luminal sperm, similar to 3.5-week-old wild-type mice, but at 8 weeks, no structural differences in the testis or epididymis were noted between InhbaBK/BK and wild-type mice. Thus, Inhbb can compensate for Inhba in regulating epididymal morphology, although testis and epididymal maturation is delayed in mice lacking Inhba. Crucially, reduction or absence of activin A, at least in the presence of normal activin B levels, does not lead to major defects in the adult epididymis or vas deferens.
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Refaat, Bassem, Adel Galal El-Shemi, Ahmed Mohamed Ashshi, and Adnan AlZanbagi. "Serum Activins and Follistatin during the Treatment of Chronic Hepatitis C Genotypes 1 and 4 and Their Correlations with Viral Load and Liver Enzymes: A Preliminary Report." Gastroenterology Research and Practice 2014 (2014): 1–9. http://dx.doi.org/10.1155/2014/628683.
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Aims. To measure the effect of pegylated interferon-αtherapy on serum activin-A, activin-B, and follistatin and their correlation with viral load and liver fibrosis in chronic hepatitis C (CHC).Methods. This study was cross-sectional and sera were collected from 165 participants classified into 7 groups: 40 healthy negative control, 33 treatment naïve patients as positive control, 19 patients at week 4, 22 at week 12, and 19 at week 24 of treatment initiation and 21 responders and 11 nonresponders at the end of 48-week treatment protocol. Serum candidate proteins were measured using ELISA and liver fibrosis was assessed by AST platelet ratio index (APRI).Results. CHC significantly increased activins and decreased follistatin compared to negative control(P<0.05). Activin-A and follistatin levels returned to the levels of negative control group at weeks 4, 12, and 24 following treatment initiation and were significantly different from positive control(P<0.05). Both proteins were significantly different between responders and nonresponders. Activin-A correlated positively and significantly with the viral load and APRI.Conclusion. CHC modulates serum activin-A and follistatin and they appear to be influenced by pegylated interferon-αtherapy. Further studies are needed to explore the role of activins in CHC.
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Glister, Claire, Simon J. Sunderland, Maurice P. Boland, James J. Ireland, and Phil G. Knight. "Comparison of bioactivities, binding properties and intrafollicular levels of bovine follistatins." REPRODUCTION 150, no. 2 (August 2015): 85–96. http://dx.doi.org/10.1530/rep-15-0086.
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Five isoforms of follistatin (FST) (Mr31, 33, 35, 37, and 41 kDa) were purified from bovine follicular fluid (bFF). Comparison of their activin and heparan sulphate proteoglycan (HSP) binding properties and biopotencies in the neutralisation of activin A actionin vitrorevealed that all five isoforms bound activin A, but they did so with different affinities. Only the 31 kDa isoform (FST-288) bound to HSP. FST-288 also showed the greatest biopotency, and the 35 and 41 kDa isoforms were the least potent. To determine whether bovine follicle development is associated with changing intrafollicular FST and activin profiles, we analysed bFF from dominant follicles (DFs) and subordinate follicles (SF) collected at strategic times during a synchronised oestrous cycle. Total FST, activin A and activin AB were measured by immunoassay, whereas individual FST isoforms were quantified by immunoblotting. Follicle diameter was positively correlated with oestrogen:progesterone ratio (r=0.56) in bFF but negatively correlated with activin A (r=−0.34), activin AB (r=−0.80) and ‘total’ FST (r=−0.70) levels. Follicle diameter was positively correlated with the abundance of the 41 kDa isoform (r=0.59) but negatively correlated with the abundance of the 33 and 31 kDa isoforms (r=−0.56 andr=−0.41 respectively). Both follicle statuses (DF and SF) and cycle stage affected total FST, activin A and activin B levels, whereas follicle status, but not cycle stage, affected the abundance of the 41, 37, 33 and 31 kDa FST isoforms. Collectively, these findings indicate that intrafollicular FST isoforms, which differ in their ability to bind and neutralise activins and to associate with cell-surface proteoglycans, show divergent changes during follicle development. Enhanced FST production may play an important negative role, either directly or via the inhibition of the positive effects of activins, on follicle growth and function during follicular waves.
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Albano, R. M., R. Arkell, R. S. Beddington, and J. C. Smith. "Expression of inhibin subunits and follistatin during postimplantation mouse development: decidual expression of activin and expression of follistatin in primitive streak, somites and hindbrain." Development 120, no. 4 (April 1, 1994): 803–13. http://dx.doi.org/10.1242/dev.120.4.803.
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Members of the activin family are believed to act as mesoderm-inducing factors during early amphibian development. Little is known, however, about mesoderm formation in the mammalian embryo, and as one approach to investigating this we have studied activin and follistatin expression during early mouse development. Activins are homo- or heterodimers of the beta A or beta B subunits of inhibin, itself a heterodimer consisting of one of the beta subunits together with an alpha subunit. Follistatin is a single-chain polypeptide which inhibits activin function. Expression of the inhibin alpha chain could not be detected in embryonic or extraembryonic tissues at any of the stages studied (5.5 to 8.5 days) and expression of the beta A and beta B subunits could only be observed in the deciduum in cells surrounding the embryo. Expression of follistatin could also be detected in the deciduum, but in a pattern complementary to that of the beta subunits. Embryonic expression of follistatin first occurred in the primitive streak, and at later stages transcripts were detectable in the somites and in rhombomeres 2, 4 and 6 of the hindbrain. These results are consistent with a role for activin in mesoderm formation in the mouse embryo, and suggest functions for follistatin in addition to its role as an inhibitor of activin.
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Reedy, Patrick C., and Daniel R. King. "Critical Performativity in the Field: Methodological Principles for Activist Ethnographers." Organizational Research Methods 22, no. 2 (December 7, 2017): 564–89. http://dx.doi.org/10.1177/1094428117744881.
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It has been proposed that engagement with activism might make critical organizational scholarship more relevant to practitioners. However, there is a lack of systematic inquiry into how such engagement might be undertaken, which this article redresses. We propose activist ethnography as a suitable methodological framework for critical organizational scholarship, drawing on organizational ethnography, militant ethnography, and participatory action research, to construct a theoretical framework which we use to analyze four ethnographic vignettes of our own experiences of research with activists. Our contribution is to (a), assess the methodological challenges and opportunities of engagement with activism, (b) give an account of our own experiences as activist ethnographers for others to learn from, and (c) propose strategies whereby the challenges of academic activism might be negotiated and the opportunities maximized.
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Robinson, G. W., and L. Hennighausen. "Inhibins and activins regulate mammary epithelial cell differentiation through mesenchymal-epithelial interactions." Development 124, no. 14 (July 15, 1997): 2701–8. http://dx.doi.org/10.1242/dev.124.14.2701.
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Inhibins and activins are members of the transforming growth factor beta (TGFbeta) family. Female mice in which both alleles encoding the inhibin betaB subunit have been deleted are unable to nurse their pups. We have now identified a cause of lactation failure in these mice. Ductal elongation and alveolar morphogenesis are retarded. During puberty and pregnancy, ductal outgrowth and alveolar development are limited and morphologically abnormal endbuds persist in the glands of postpartum females. The alveolar lumina fail to expand at parturition due to the absence of secreted milk. Transplantation experiments have been performed to determine whether the absence of systemic- or mammary-derived betaB subunits are the cause for the incomplete and aberrant development. While transplanted intact glands from wild-type mice grew normally in betaB-deficient hosts, betaB-deficient glands remained underdeveloped in wild-type hosts. However, betaB-deficient epithelium developed normally when transplanted into the fat pad of wild-type hosts. This demonstrates that ductal elongation and epithelial cell differentiation during puberty and pregnancy require activin/inhibin signalling from the stroma. The results further show that distinct, though related, activins and inhibins perform unique functions and are not able to compensate for the absence of activin B and AB and inhibin B in the process of mammogenesis. The betaB-deficient mice provide the first genetic evidence for stromal signalling in the adult mammary gland in vivo.
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Walton, Kelly L., Justin L. Chen, Quinn Arnold, Emily Kelly, Mylinh La, Louis Lu, George Lovrecz, et al. "Activin A–Induced Cachectic Wasting Is Attenuated by Systemic Delivery of Its Cognate Propeptide in Male Mice." Endocrinology 160, no. 10 (July 19, 2019): 2417–26. http://dx.doi.org/10.1210/en.2019-00257.
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Abstract In cancer, elevated activin levels promote cachectic wasting of muscle, irrespective of tumor progression. In excess, activins A and B use the myostatin signaling pathway in muscle, triggering a decrease in protein synthesis and an increase in protein degradation, which ultimately leads to atrophy. Recently, we demonstrated that local delivery of engineered activin and myostatin propeptides (natural inhibitors of these growth factors) could induce profound muscle hypertrophy in healthy mice. Additionally, the expression of these propeptides effectively attenuated localized muscle wasting in models of dystrophy and cancer cachexia. In this study, we examined whether a systemically administered recombinant propeptide could reverse activin A–induced cachectic wasting in mice. Chinese hamster ovary cells stably expressing activin A were transplanted into the quadriceps of nude mice and caused an 85-fold increase in circulating activin A levels within 12 days. Elevated activin A induced a rapid reduction in body mass (−16%) and lean mass (−10%). In agreement with previous findings, we demonstrated that adeno-associated virus–mediated delivery of activin propeptide to the tibialis anterior muscle blocked activin-induced wasting. In addition, despite massively elevated levels of activin A in this model, systemic delivery of the propeptide significantly reduced activin-induced changes in lean and body mass. Specifically, recombinant propeptide reversed activin-induced wasting of skeletal muscle, heart, liver, and kidneys. This is the first study to demonstrate that systemic administration of recombinant propeptide therapy effectively attenuates tumor-derived activin A insult in multiple tissues.
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Lee, Katharine B., Vishal Khivansara, Michelle M. Santos, Pankaj Lamba, Tony Yuen, Stuart C. Sealfon, and Daniel J. Bernard. "Bone morphogenetic protein 2 and activin A synergistically stimulate follicle-stimulating hormone β subunit transcription." Journal of Molecular Endocrinology 38, no. 2 (February 2007): 315–30. http://dx.doi.org/10.1677/jme.1.02196.
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Transforming growth factor β superfamily ligands regulate pituitary FSH production and secretion. The best-described examples are the activins and inhibins, which respectively stimulate and hinder Fshb subunit transcription in gonadotrope cells. More recently, members of the bone morphogenetic protein (BMP) sub-family were shown to regulate FSH production in a manner analogous to the activins. Here, we used the murine gonadotrope cell line, LβT2, to investigate mechanisms through which BMP2 regulates the Fshb gene. Although expressed at low levels in LβT2 cells, Bmp2 mRNA was readily detected in adult murine pituitary gland. Recombinant BMP2 stimulated Fshb promoter-reporter activity, although its effects were weaker than those of equimolar activin A or B. BMP4 stimulated transcription comparably with BMP2, but BMPs 6 and 7 were about tenfold less potent. Remarkably, BMP2 and activin A synergistically upregulated Fshb transcription and endogenous Fshb mRNA levels in LβT2 cells. Although functionally cooperative, the two ligands appeared to use distinct intracellular mechanisms to mediate their responses because neither ligand altered the timing or magnitude of the other’s effects. Receptor overexpression analyses suggested that BMP2 may preferentially signal through complexes of the type II receptor, BMPR2, and the type I receptor, activin receptor like kinase (ALK2; Acvr1), to stimulate Fshb transcription. BMP2 rapidly activated the Smad1/5/8 intracellular signaling cascade and Smad8 overexpression potentiated BMP2’s effects. In summary, BMPs regulate Fshb transcription in LβT2 cells and can amplify the already robust effects of the activins through a distinct signaling mechanism. Because BMP2 is expressed in the adult mouse pituitary, it may act as critical paracrine co-regulator of FSH synthesis by gonadotropes.
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Robertson, D. M., H. G. Burger, and P. J. Fuller. "Inhibin/activin and ovarian cancer." Endocrine-related cancer 11, no. 1 (March 2004): 35–49. http://dx.doi.org/10.1677/erc.0.0110035.
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Inhibin and activin are members of the transforming growth factor beta (TGFbeta) family of cytokines produced by the gonads, with a recognised role in regulating pituitary FSH secretion. Inhibin consists of two homologous subunits, alpha and either betaA or betaB (inhibin A and B). Activins are hetero- or homodimers of the beta-subunits. Inhibin and free alpha subunit are known products of two ovarian tumours (granulosa cell tumours and mucinous carcinomas). This observation has provided the basis for the development of a serum diagnostic test to monitor the occurrence and treatment of these cancers. Transgenic mice with an inhibin alpha subunit gene deletion develop stromal/granulosa cell tumours suggesting that the alpha subunit is a tumour suppressor gene. The role of inhibin and activin is reviewed in ovarian cancer both as a measure of proven clinical utility in diagnosis and management and also as a factor in the pathogenesis of these tumours. In order to place these findings into perspective the biology of inhibin/activin and of other members of the TGFbeta superfamily is also discussed.
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Panagiotou, Grigorios, Wael Ghaly, Jagriti Upadhyay, Kalliopi Pazaitou-Panayiotou, and Christos S. Mantzoros. "Serum Follistatin Is Increased in Thyroid Cancer and Is Associated With Adverse Tumor Characteristics in Humans." Journal of Clinical Endocrinology & Metabolism 106, no. 5 (January 25, 2021): e2137-e2150. http://dx.doi.org/10.1210/clinem/dgab041.
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Abstract Context Obesity and classical growth factors are associated with thyroid cancer (TC). However, less is known regarding novel hormones such as follistatins and activins. We hypothesized that serum follistatin but not activins would be increased in TC. Objective This work aimed to assess circulating levels of follistatins, activins, and growth factors in patients with a history of TC vs patients with nonmalignant thyroid diseases. Methods A hospital-based, unmatched case-control study was conducted with 170 thyroidectomized patients due to well-differentiated TC and 106 thyroidectomized patients without history of malignancy. Anthropometric, biochemical, and histological parameters were recorded. Serum samples were collected in the steady state 45 days after surgery. Multivariate models were used to adjust for baseline differences of the unmatched variables. Serum levels of follistatin (FST), follistatin like-3, activin A, activin B, bioactive insulin-like growth factor-1, and stanniocalcin-2 were assayed with novel, highly specific ELISA kits. Results In unmatched univariate models, TC patients had higher FST serum levels compared to cancer-free individuals, independently of histological subtype. In multivariate models adjusting for covariates, individuals in the highest tertile of FST levels were associated with an increased risk for the presence of any type of TC or specific histological subtypes, including papillary, follicular and Hürthle-cell carcinoma, and medullary TC. Higher postoperative FST concentrations were found in patients with vascular invasion and distant metastases and associated with TNM staging at diagnosis. Conclusion FST serum levels are increased in TC patients and correlate with advanced tumor aggressiveness. Future longitudinal studies are needed to confirm and extend our observations.
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Wang, Ying, Vanessa Libasci, and Daniel J. Bernard. "Activin A induction of FSHβ subunit transcription requires SMAD4 in immortalized gonadotropes." Journal of Molecular Endocrinology 44, no. 6 (April 6, 2010): 349–62. http://dx.doi.org/10.1677/jme-09-0142.
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Activins regulate FSH synthesis by stimulating the phosphorylation and nuclear accumulation of SMAD2 and SMAD3, which bind to a consensus SMAD-binding element in the proximal murine FSHβ (Fshb) subunit gene to drive transcription. Previous over-expression and in vitro DNA binding analyses suggested that SMAD4 participates in complexes with SMAD2 and SMAD3 to regulate Fshb expression. Here, we have characterized the role of endogenous SMAD4 in activin A induction of Fshb transcription in immortalized murine gonadotropes (LβT2). We identified five murine Smad4 mRNA isoforms, of which, four are newly described; however, the canonical full-length form predominated at both the mRNA and protein levels. Depletion of endogenous SMAD4 by RNA interference (RNAi) abolished activin A-induced Fshb promoter-reporter activity and greatly attenuated constitutively active activin type IB receptor-stimulated Fshb mRNA levels. The activin A response was rescued with an RNAi-resistant form of wild-type SMAD4, but not with a DNA-binding-deficient (Lys88Arg) SMAD4, suggesting that DNA binding by SMAD4 is necessary for activin induction of the Fshb gene. Though SMAD2 and SMAD3 are generally thought to partner with SMAD4 prior to accumulation in the nucleus, treatment with leptomycin B, an inhibitor of SMAD4 nuclear export, reduced but did not prevent activin A induction of Fshb mRNA levels or promoter activity. In addition, a constitutively nuclear form of SMAD4 rescued the effect of endogenous SMAD4 depletion. Collectively, these data demonstrate a necessary role for SMAD4 in activin A induction of the murine Fshb gene in immortalized gonadotropes.
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Steinbeisser, H., E. M. De Robertis, M. Ku, D. S. Kessler, and D. A. Melton. "Xenopus axis formation: induction of goosecoid by injected Xwnt-8 and activin mRNAs." Development 118, no. 2 (June 1, 1993): 499–507. http://dx.doi.org/10.1242/dev.118.2.499.
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In this study, we compare the effects of three mRNAs-goosecoid, activin and Xwnt-8- that are able to induce partial or complete secondary axes when injected into Xenopus embryos. Xwnt-8 injection produces complete secondary axes including head structures whereas activin and goosecoid injection produce partial secondary axes at high frequency that lack head structures anterior to the auditory vesicle and often lack notochord. Xwnt-8 can activate goosecoid only in the deep marginal zone, i.e., in the region in which this organizer-specific homeobox gene is normally expressed on the dorsal side. Activin B mRNA, however, can turn on goosecoid in all regions of the embryo. We also tested the capacity of these gene products to restore axis formation in embryos in which the cortical rotation was blocked by UV irradiation. Whereas Xwnt-8 gives complete rescue of anterior structures, both goosecoid and activin give partial rescue. Rescued axes including hindbrain structures up to level of the auditory vesicle can be obtained at high frequency even in the absence of notochord structures. The possible functions of Wnt-like and activin-like signals and of the goosecoid homeobox gene, and their order of action in the formation of Spemann's organizer are discussed.
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Repo, Jemima. "Feminist Commodity Activism: The New Political Economy of Feminist Protest." International Political Sociology 14, no. 2 (January 17, 2020): 215–32. http://dx.doi.org/10.1093/ips/olz033.
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Abstract This article theorizes the commodification of the recent resurgence of feminist activism through the concept of “feminist commodity activism.” The focus is on the mass popularization of feminist-themed commodities, with T-shirts as a particular focus. First, I discuss how the mass marketing of feminist goods ties in with: (a) commodity feminism, by refetishizing commodities and consumption as empowering for women; (b) neoliberal feminism, through the construction of the feminist as an economic and choice-making subject; and (c) commodity activism, by entangling feminism with the discourses and practices of ethical consumption. Building on these concepts, I propose “feminist commodity activism” as a way to capture and further analyze the current commodification of feminism activism occurring at their intersection. I argue that feminist commodity activism instigates three further shifts: the commodification of the aesthetic experience of feminist street protest; the transfer of feminist activist agency to companies, charities, and entrepreneurs; and the branding of the feminist as a subject of value. Finally, the article considers the challenges that these shifts pose for feminist critique and politics.
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Li, M. D., G. J. MacDonald, and J. J. Ford. "Breed Differences in Expression of Inhibin/Activin Subunits in Porcine Anterior Pituitary Glands*." Endocrinology 138, no. 2 (February 1, 1997): 712–18. http://dx.doi.org/10.1210/endo.138.2.4949.
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Abstract Chinese Meishan (MS) boars have greater plasma FSH concentrations than European White Composite boars, but this difference does not occur in females of these breeds. To understand this disparity, we studied expression of the follistatin gene and of genes for the inhibin/activinα -, βA-, and βB-subunits in porcine anterior pituitary glands using quantitative reverse transcription-PCR and ribonuclease protection techniques. We found that 1) the inhibin/activin βA- and βB-subunits and follistatin were expressed in porcine pituitary; 2) the α-subunit was not detected in the porcine pituitary, but was highly expressed in porcine follicles; and 3) the βB-subunit gene is more abundantly expressed (2-fold greater) in MS boar pituitaries than in pituitaries of White Composite boars. We conclude that this is not due to a breed difference, because the expression levels of this gene were similar in pituitaries of females of these breeds. No breed differences were detected for other genes screened in this study. From these observations, we propose that activin B, a dimer ofβ B-subunits and a stimulator of FSH secretion, may be partially responsible for the elevated plasma FSH concentrations in MS boars, and intrapituitary inhibin plays no or a very minimal role.
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Canali, Susanna, Amanda B. Core, Kimberly B. Zumbrennen-Bullough, Maria Merkulova, Chia-Yu Wang, Alan L. Schneyer, Antonello Pietrangelo, and Jodie L. Babitt. "Activin B Induces Noncanonical SMAD1/5/8 Signaling via BMP Type I Receptors in Hepatocytes: Evidence for a Role in Hepcidin Induction by Inflammation in Male Mice." Endocrinology 157, no. 3 (January 6, 2016): 1146–62. http://dx.doi.org/10.1210/en.2015-1747.
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Abstract Induction of the iron regulatory hormone hepcidin contributes to the anemia of inflammation. Bone morphogenetic protein 6 (BMP6) signaling is a central regulator of hepcidin expression in the liver. Recently, the TGF-β/BMP superfamily member activin B was implicated in hepcidin induction by inflammation via noncanonical SMAD1/5/8 signaling, but its mechanism of action and functional significance in vivo remain uncertain. Here, we show that low concentrations of activin B, but not activin A, stimulate prolonged SMAD1/5/8 signaling and hepcidin expression in liver cells to a similar degree as canonical SMAD2/3 signaling, and with similar or modestly reduced potency compared with BMP6. Activin B stimulates hepcidin via classical activin type II receptors ACVR2A and ACVR2B, noncanonical BMP type I receptors activin receptor-like kinase 2 and activin receptor-like kinase 3, and SMAD5. The coreceptor hemojuvelin binds to activin B and facilitates activin B-SMAD1/5/8 signaling. Activin B-SMAD1/5/8 signaling has some selectivity for hepatocyte-derived cells and is not enabled by hemojuvelin in other cell types. Liver activin B mRNA expression is up-regulated in multiple mouse models of inflammation associated with increased hepcidin and hypoferremia, including lipopolysaccharide, turpentine, and heat-killed Brucella abortus models. Finally, the activin inhibitor follistatin-315 blunts hepcidin induction by lipopolysaccharide or B. abortus in mice. Our data elucidate a novel mechanism for noncanonical SMAD activation and support a likely functional role for activin B in hepcidin stimulation during inflammation in vivo.
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Braun, Jolie. "Make Your Own History: Documenting Feminist & Queer Activism in the 21st Century. Eds. Lyz Bly and Kelly Wooten. Los Angeles: Litwin Books, 2012. xi, 180p. $30 (ISBN978-1-936117-13-0)." RBM: A Journal of Rare Books, Manuscripts, and Cultural Heritage 14, no. 1 (March 1, 2013): 48–50. http://dx.doi.org/10.5860/rbm.14.1.399.
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Make Your Own History: Documenting Feminist & Queer Activism in the 21st Century, edited by Lyz Bly and Kelly Wooten, features essays by archivists, librarians, and activists that explore collecting, preserving, and providing access to materials produced by contemporary feminist and queer activist movements. Thought provoking and informative, this collection will be useful to archivists, librarians, activists, and scholars interested in women’s and LGBT history; and, despite the book’s particular focus, the best essays in this anthology will be useful to archivists and librarians throughout the field.Several of the essays in the book focus on collecting zines of the . . .
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Gravelsina, Sabine, Zaiga Nora-Krukle, Anda Vilmane, Simons Svirskis, Katrine Vecvagare, Angelika Krumina, and Modra Murovska. "Potential of Activin B as a Clinical Biomarker in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)." Biomolecules 11, no. 8 (August 11, 2021): 1189. http://dx.doi.org/10.3390/biom11081189.
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Reliable serum biomarkers are of immense need for diagnostic purposes of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)—a disabling and complex disease for which diagnosis is mainly based on clinical symptoms. The aim of this study was to evaluate a possible diagnostic potential of activin B by directly comparing 134 cases of ME/CFS with 54 healthy controls. Analyses of human activin B level in plasma samples were performed using a validated human activin B ELISA assay. The results of the study show that activin B levels did not differ statistically significantly between ME/CFS patients and healthy controls (p = 0.6511). No gender or age-related differences in activin B levels were observed in the ME/CFS group and healthy controls. The level of activin B tended to decrease with increasing visual analogue scale score (r = −0.2004; p = 0.5085) nevertheless the results obtained so far does not support the clinical utility of activin B as a biomarker for ME/CFS.
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Dander, Erica, Federica Portale, Daniela Silvestri, Giulia Cricrì, Silvia Bresolin, Stefania Gaspari, Barbara Russo, et al. "Activin A, a Potential Key Factor of the Malignant Bone Marrow Niche, Enhances B-Cell Precursor-Acute Lymphoblastic Leukemic Cell Migratory and Invasive Properties." Blood 132, Supplement 1 (November 29, 2018): 1296. http://dx.doi.org/10.1182/blood-2018-99-116668.
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Abstract The bone marrow (BM) represents a peculiar microenvironment characterized by a high concentration of growth factors and cytokines necessary for hematopoiesis, that make it a sanctuary for leukemic cell homing, survival and proliferation. B-cell precursor-Acute Lymphoblastic Leukemia (BCP-ALL) reprogram the BM stroma to create a leukemia-supporting and chemoprotective niche. Strategies to modulate the microenvironment could offer new approaches for anti-leukemia therapies. We identified ActivinA, a TGF-β family member, with a well-described promoting role in several solid malignancies, as a new potentially targetable leukemia-favoring factor. ActivinA resulted overexpressed in the BM plasma of 108 BCP-ALL pediatric patients compared to 44 Healthy Donors (HDs), as evaluated by ELISA assay. Upon in vitro culture, primary BCP-ALL cells significantly increased ActivinA secretion by mesenchymal stromal cells (MSCs) derived from HD BM. Interestingly this effect was achieved both by cell-to-cell contact-mediated mechanisms (direct contact) and by soluble factor release (transwell-mediated co-culture). Interestingly, MSCs isolated from the BM of leukemic patients showed an intrinsic ability to secrete higher amounts of ActivinA (mean=983.6±362.9 pg/mL), compared to their normal counterpart (mean=218.5±31.99 pg/mL). In addition, we demonstrated that the pro-inflammatory cytokines IL-1β, IL-6 and TNF-α are increased in the leukemic BM and that they were able to synergize with leukemic blasts in inducing ActivinA release by MSCs (>100 fold increase compared to basal production). Both type I and type II Activin receptors were found to be expressed by leukemic cells as demonstrated by flow cytometry analysis of ALK4, ACVR2A and ACVR2B receptors and western blot analysis of ALK2. Of note, ActivinA exposure could increase the mRNA expression levels of type I receptors ALK2 and ALK4, thus suggesting a possible self-reinforcing mechanism. Gene expression analysis of ActivinA-treated BCP-ALL cells showed that this protein was able to significantly influence motility-associated molecular pathways. Accordingly, time lapse microscopy analyses revealed that ActivinA significantly increased random motility of leukemic cells (p<0.0001). In addition, ActivinA was able to almost double the migration of BCP-ALL primary cells in response to CXCL12, as demonstrated by in vitro chemotaxis assays. The specificity of the observed effect was demonstrated by using the ALK4 specific inhibitor SB431542. CXCL12 reduction is one of the typical microenvironmental alterations occurring in the leukemic BM. In line with literature data, we showed 6-fold decrese of CXCL12 levels in the BM of BCP-ALL patients compared to HDs (p<0.0001). Dose-responses chemotaxis experiments revealed that ActivinA was able to sensitize leukemic cells to suboptimal CXCL12 concentrations. On the other site, ActivinA exerted an opposite effect on CD34+ cells isolated both from HD cord blood or BM. In detail, in HD-CD34+ cells ActivinA severely impaired CXCL12-induced migration (p<0.0001). This opposite effect could be explained by ActivinA ability to increase free cytosolic calcium only in leukemic cells, both basally and after addition of CXCL12 (flow cytometry analysis of Fluo-4 NW stained cells). Of note, calcium levels of HD-CD34+ cells resulted unaffected or even decreased (in 2 out of 3 experiments performed) by ActivinA treatment. Since calcium is critically involved in boosting cytoskeleton dynamics, we analysed, by flow cytometry, actin polymerization in phalloidin stained BCP-ALL cells. Interestingly, ActivinA treatment of BCP-ALL cells significantly increased the rate of conversion of globular into filamentous actin, which is a prerequisite of site-directed migration, as soon as CXCL12 was added. Moreover, ActivinA resulted a leukemia-promoting factor: protein treatment significantly increased the in vitro migration of BCP-ALL cells through Matrigel-coated transwells in response to CXCL12, thus stimulating leukemic cell invasiveness. Overall, ActivinA resulted a key factor conferring a migratory advantage to leukemic cells over healthy hematopoiesis within the leukemic niche. Indeed, our in vitro findings provide the biological rationale for designing novel therapeutical approaches targeting the leukemia-stroma interplay. Disclosures Locatelli: bluebird bio: Consultancy; Bellicum: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Miltenyi: Honoraria.
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Okuma, Y., A. E. O’Connor, T. Hayashi, K. L. Loveland, D. M. de Kretser, and M. P. Hedger. "Regulated production of activin A and inhibin B throughout the cycle of the seminiferous epithelium in the rat." Journal of Endocrinology 190, no. 2 (August 2006): 331–40. http://dx.doi.org/10.1677/joe.1.06706.
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Production and regulation of activin A and inhibin B during the cycle of the seminiferous epithelium were investigated in adult rats. Immunohistochemistry localised the activin βA-subunit to the Sertoli cell cytoplasm, with much weaker expression in spermatocytes and spermatids. Both activin A and inhibin B, measured by ELISA were secreted by, seminiferous tubule fragments over 72 h in culture. Activin A was secreted in a cyclic manner with peak secretion from tubules isolated at stage VIII. Tubules collected during stage VI produced the least activin A. Inhibin B secretion was highest from stage IX-I tubules and lowest from stage VII tubules. Addition of interleukin-1β (IL-1β) had relatively little effect on activin A or inhibin B secretion in culture. In contrast, the peak secretion of activin A by stage VIII tubules was blocked by co-incubation with an excess of human recombinant IL-1 receptor antagonist, whereas inhibin B secretion increased slightly. Dibutyryl cAMP stimulated activin A secretion by late stage VII and VIII tubules and stimulated inhibin B across all stages. These data indicate that activin A and inhibin B are cyclically regulated within the seminiferous epithelium, with endogenous IL-1 (presumably IL-1α produced by the Sertoli cells), responsible for a peak of activin A production subsequent to sperm release at stage VIII. These data provide direct evidence that production of activin A and inhibin B by the Sertoli cell is locally modulated by IL-1α , in addition to FSH/cAMP, under the influence of the developing spermatogenic cells.
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Vanttinen, T., J. Liu, J. Liu, C. Hyden-Granskog, M. Parviainen, I. Penttila, and R. Voutilainen. "Regulation of immunoreactive inhibin A and B secretion in cultured human granulosa-luteal cells by gonadotropins, activin A and insulin-like growth factor type-1 receptor." Journal of Endocrinology 167, no. 2 (November 1, 2000): 289–94. http://dx.doi.org/10.1677/joe.0.1670289.
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Inhibins are gonadal glycoproteins with endocrine effects on pituitary FSH secretion and para/autocrine effects on ovarian and testicular function. The purpose of this study was to investigate the endocrine and para/autocrine regulation of inhibin A and inhibin B secretion in human ovarian granulosa-luteal cells. The cells were obtained from women undergoing in vitro fertilization, and the primary cultures were treated with FSH, LH, human chorionic gonadotropin (hCG), activin A, 8-bromo cyclic AMP (8-BrcAMP), staurosporine (a protein kinase C inhibitor) and an antagonist of IGF action (type-1 IGF receptor antibody alpha IR3). The secretion of inhibins was measured by ELISA assays capable of reliably distinguishing between inhibin A and B. FSH, LH, hCG and 8-BrcAMP increased inhibin A secretion on average up to 180% (P<0.01), 192% (P<0.05), 210% (P<0.01) and 243% (P<0.01) respectively of the control level, while their stimulatory effect on inhibin B secretion was less pronounced (up to 167%, P<0.01; 139%, P<0.05; 127%, P>0.05; 133%, P>0.05 of the controls respectively). alpha IR3 decreased inhibin A and B secretion down to 70% (P<0.01) and 50% (P<0.01) respectively of the control. Staurosporine decreased inhibin B secretion down to 49% (P<0.01) of the control; its effect on inhibin A secretion was not significant. Activin A increased inhibin B secretion up to fourfold of the control (P<0.05) while its effect on inhibin A secretion was insignificant. We conclude that gonadotropins via the protein kinase A signal transduction pathway are the main positive regulators of inhibin A and B secretion in human granulosa-luteal cells. The protein kinase C signal transduction pathway seems to be important especially for inhibin B secretion. Locally produced IGFs are probably important inducers of the production of both forms of inhibin in human ovaries while activins seem to upregulate inhibin B secretion.
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Knight, P. G., S. Muttukrishna, and N. P. Groome. "Development and application of a two-site enzyme immunoassay for the determination of 'total' activin-A concentrations in serum and follicular fluid." Journal of Endocrinology 148, no. 2 (February 1996): 267–79. http://dx.doi.org/10.1677/joe.0.1480267.
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Abstract The performance of existing immunoassays and bioassays for activins is compromised by the presence of activin-binding proteins such as follistatin and α2 macroglobulin (α2M) in biological fluids. To overcome this problem we have developed a novel two-site enzyme immunoassay procedure for activin-A which incorporates an analyte denaturation and oxidation step. The optimized assay is sensitive (detection limit ∼10 pg/well), precise (mean within- and between-plate coefficients of variation 4·9 and 9·1% respectively) and accurate (activin-A recovery values of 102 ± 3 and 96 ± 5% for bovine follicular fluid (FF) and human serum respectively). In specificity tests, high concentrations of follistatin (500 ng/ml) and α2M (100 μg/ml) did not interfere with the response signal to activin-A. In addition, no significant cross-reactivity was observed with a range of related molecules including inhibin-A, inhibin-B, activin-B (all <0·5%), bovine pro-αC and follistatin (both <0·1%). Response curves parallel to the activin-A standard curve were obtained for a variety of test samples including bovine, human, ovine and porcine FF, human sera and conditioned medium from cultured bovine and human granulosa cells. Fractionation of bovine FF by SDS-PAGE confirmed assay specificity since only one peak of activin-A immunoreactivity was detected (Mr ∼25 k) in eluted gel slices. However, gel-permeation chromatography showed that under physiological conditions all of the detectable activin-A in bovine FF eluted with apparent Mr values of >700 and 60–200 k reflecting its association with binding protein(s). Analysis of bovine FF samples (n=76) from morphologically dominant follicles during the luteal phase showed that activin-A levels were positively correlated with inhibin-A (r=+0·54; P<0·001) and total β subunit immunoreactivity (r=+0·32; P<0·005) but not with total α subunit immunoreactivity (r= −0·09). Classification of these follicles according to oestrogenic status showed that activin-A, inhibin-A and total β subunit levels were highest in oestrogen-inactive follicles (P<0·01) whereas total α subunit levels were lowest in these follicles (P<0·001). Activin-A levels were measurable in all human serum samples analysed, ranging from 128 pg/ml during the normal menstrual cycle, 210 pg/ml in women undergoing ovarian hyperstimulation and ∼ 500 pg/ml in postmenopausal women to over 4000 pg/ml during pregnancy. In conclusion, the present assay provides a reliable method for quantitating total (i.e. bound+free) activin-A concentrations in a variety of biological samples and should prove useful for further in vivo and in vitro studies in a range of species including man. Journal of Endocrinology (1996) 148, 267–279
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Dale, L., G. Howes, B. M. Price, and J. C. Smith. "Bone morphogenetic protein 4: a ventralizing factor in early Xenopus development." Development 115, no. 2 (June 1, 1992): 573–85. http://dx.doi.org/10.1242/dev.115.2.573.
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The mesoderm of amphibian embryos such as Xenopus laevis arises through an inductive interaction in which cells of the vegetal hemisphere of the embryo act on overlying equatorial and animal pole cells. Three classes of ‘mesoderm-inducing factor’ (MIF) that might be responsible for this interaction in vivo have been discovered. These are members of the transforming growth factor type beta (TGF-beta), fibroblast growth factor (FGF) and Wnt families. Among the most potent MIFs are the activins, members of the TGF-beta family, but RNA for activin A and B is not detectable in the Xenopus embryo until neurula and late blastula stages, respectively, and this is probably too late for the molecules to act as natural inducers. In this paper, we use the polymerase chain reaction to clone additional members of the TGF-beta family that might possess mesoderm-inducing activity. We show that transcripts encoding Xenopus bone morphogenetic protein 4 (XBMP-4) are detectable in the unfertilized egg, and that injection of XBMP-4 RNA into the animal hemisphere of Xenopus eggs causes animal caps isolated from the resulting blastulae to express mesoderm-specific markers. Surprisingly, however, XBMP-4 preferentially induces ventral mesoderm, whereas the closely related activin induces axial tissues. Furthermore, the action of XBMP-4 is ‘dominant’ over that of activin. In this respect, XBMP-4 differs from basic FGF, another ventral inducer, where simultaneous treatment with FGF and activin results in activin-like responses. The dominance of XBMP-4 over activin may account for the ability of injected XBMP-4 RNA to ‘ventralize’ whole Xenopus embryos. It is interesting, however, that blastopore formation in such embryos can occur perfectly normally. This contrasts with embryos ventralized by UV-irradiation and suggests that XBMP-4-induced ventralization occurs after the onset of gastrulation.
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Polyzos, Stergios A., Nikolaos Perakakis, Chrysoula Boutari, Jannis Kountouras, Wael Ghaly, Athanasios D. Anastasilakis, Asterios Karagiannis, and Christos S. Mantzoros. "Targeted Analysis of Three Hormonal Systems Identifies Molecules Associated with the Presence and Severity of NAFLD." Journal of Clinical Endocrinology & Metabolism 105, no. 3 (November 6, 2019): e390-e400. http://dx.doi.org/10.1210/clinem/dgz172.
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Abstract Aims To investigate circulating levels and liver gene expression of 3 hormonal pathways associated with obesity, insulin resistance, and inflammation to identify leads towards potential diagnostic markers and therapeutic targets in patients with nonalcoholic fatty liver disease (NAFLD). Methods We compared circulating levels of (1) proglucagon-derived hormones (glucagon-like peptide [GLP]-1, GLP-2, glicentin, oxyntomodulin, glucagon, major proglucagon fragment [MPGF]), (2) follistatins-activins (follistatin-like [FSTL]3, activin B), (3) IGF axis (insulin-like growth factor [IGF]-1, total and intact IGF binding protein [IGFBP]-3 and IGFBP-4, and pregnancy-associated plasma protein [PAPP]-A) in 2 studies: (1) 18 individuals with early stage NAFLD versus 14 controls (study 1; early NAFLD study) and in (2) 31 individuals with biopsy proven NAFLD (15 with simple steatosis [SS] and 16 with nonalcoholic steatohepatitis [NASH]), vs 50 controls (24 lean and 26 obese) (study 2). Liver gene expression was assessed in 22 subjects (12 controls, 5 NASH, 5 NASH-related cirrhosis). Results Patients in early stages of NAFLD demonstrate higher fasting MPGF and lower incremental increase of glicentin during oral glucose tolerance test than controls. In more advanced stages, FSTL3 levels are higher in NASH than simple steatosis and, within NAFLD patients, in those with more severe lobular and portal inflammation. The IGF-1/intact IGFBP-3 ratio is lower in patients with liver fibrosis. Genes encoding follistatin, activin A, activin B, and the IGF-1 receptor are higher in NASH. Conclusion MPGF and glicentin may be involved in early stages of NAFLD, whereas FSTL3 and IGF-1/intact IGFBP3 in the progression to NASH and liver fibrosis respectively, suggesting potential as diagnostic markers or therapeutic targets.
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Wacker, Ingrid, Martin Sachs, Karl Knaup, Michael Wiesener, Jörg Weiske, Otmar Huber, Ziya Akçetin, and Jürgen Behrens. "Key Role for Activin B in Cellular Transformation after Loss of the von Hippel-Lindau Tumor Suppressor." Molecular and Cellular Biology 29, no. 7 (January 21, 2009): 1707–18. http://dx.doi.org/10.1128/mcb.01184-07.
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ABSTRACT The von Hippel-Lindau tumor suppressor gene (VHL) is mutated in clear cell renal cell carcinomas (RCC), leading to the activation of hypoxia-inducible factor (HIF)-mediated gene transcription. Several VHL/HIF targets, such as glycolysis, angiogenesis, cell growth, and chemotaxis of tumor cells, have been implicated in the transformed phenotype of RCC-regulating properties. Here, we show that VHL suppresses key features of cell transformation through downregulation of the HIF-dependent expression of activin B, a member of the transforming growth factor β superfamily. Activin B expression is repressed by restoration of VHL in VHL-deficient RCC cells and upregulated by hypoxia. RCC tumor samples show increased expression of activin B compared to that in the normal kidney. VHL increases cell adhesion to the extracellular matrix, promotes cell flattening, and reduces invasiveness. These effects are completely phenocopied by RNA interference-mediated knockdown of activin B and reverted by treatment with recombinant activin B. Finally, knockdown of activin B reduces tumor growth of RCC cells in nude mice. Our data indicate that activin B is a key mediator of VHL/HIF-induced transformation in RCC.
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Farnworth, Paul G., Yao Wang, Pauline Leembruggen, Guck T. Ooi, Craig Harrison, David M. Robertson, and Jock K. Findlay. "Rodent adrenocortical cells display high affinity binding sites and proteins for inhibin A, and express components required for autocrine signalling by activins and bone morphogenetic proteins." Journal of Endocrinology 188, no. 3 (March 2006): 451–65. http://dx.doi.org/10.1677/joe.1.06444.
Full textAbstract:
Inhibins are expressed in the adrenal cortex, but little is known of their binding or role in the adrenal. The aims of the present study were, first, to establish whether a mouse adrenocortical (AC) cell line expresses inhibins/activins and bone morphogenetic proteins (BMP), along with proteins required for inhibin to antagonise activin and BMP actions and, secondly, to characterise and compare inhibin binding sites and proteins in the rat adrenal gland and AC cells. AC cells were found to: (1) express mRNA for multiple BMPs (BMP-2, -3, -4, -6, -8a), growth/differentiation factors (GDF-1, -3, -5, -9), Lefty A and B, and the inhibin α, βA and βB subunits (2) secrete inhibin A and inhibin B and (3) express mRNA encoding the inhibin co-receptor, betaglycan, along with activin and BMP type I (ALK2–7) and type II (ActRII, ActRIIB, BMPRII) receptors, and binding proteins (follistatin, BAMBI, gremlin). When applied to sections of rat adrenal glands, [125I]inhibin A specifically bound to cells of the adrenal cortex, mainly in the zona reticularis. Scatchard analyses of in vitro [125I]inhibin A binding to dispersed rat adrenal cells and AC cells revealed sites of high affinity (Kd(1) of 0.18 and 0.15 nM, respectively) and low affinity (Kd(2) of 2.6 and 1.3 nM, respectively. Competition for [125I]inhibin A binding by activin A or B (30 nM) was negligible, whereas BMP-2, -6 and -7 competed for between 21 and 33% of specific inhibin A binding (IC50 between 0.2 and 0.3 nM). Inhibin B crossreaction with inhibin A binding sites was < 8%. Multiple binding protein complexes (molecular weight ranging from 35 to > 220 kDa) were affinity labelled by [125I]inhibin A on both the primary rat adrenal and AC cells. The species of > 220 kDa were shown by immunoprecipitation to include betaglycan, the species of 105 kDa is consistent in size with type II receptors for activin/BMP, and that of 62 kDa co-migrates with the inhibin-follistatin complex. In summary, the results show that inhibin A binds selectively and with both high and low affinity to AC cells via multiple binding proteins, including a single betaglycan-like species. The results support the role of glycosylated betaglycan in the high affinity binding of inhibin A, but provide consistent evidence from two independent sources of adrenal cells that inhibin A interacts with several membrane proteins in addition to those currently understood to mediate the anti-activin/BMP actions of inhibin.
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Suzuki, A., T. Nagai, S. I. Nishimatsu, H. Sugino, Y. Eto, H. Shibai, K. Murakami, and N. Ueno. "Autoinduction of activin genes in early Xenopus embryos." Biochemical Journal 298, no. 2 (March 1, 1994): 275–80. http://dx.doi.org/10.1042/bj2980275.
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Activin exhibits a potent mesoderm inducing activity towards the ectodermal tissue (animal cap) of Xenopus laevis blastulae. Thus in order to investigate the role of activin in morphogenesis of early Xenopus embryos, activation of genes for activin beta A and beta B was examined by the reverse transcription polymerase chain reaction. In vivo, activin beta B mRNA appears to be present in embryonic stage 1 whereas beta A mRNA is undetectable prior to gastrulation. beta B and beta A mRNAs were noted to accumulate after stages 9 and 15 respectively. Activin gene expression in Xenopus animal caps was examined after treatment with various concentrations of activin A. Under these treatment conditions, both activin beta A and beta B mRNAs accumulated in a dose-dependent fashion after 24 h. The same effect was noted for treatment with similar concentrations of activin B. Accumulation of mRNAs was inhibited by the addition of cycloheximide to the culture medium, consistent with the proposition that activin gene expression requires certain protein factors. In total, therefore, these data suggest that an autoinduction mechanism is involved in the regulation of activin mRNA levels in normal Xenopus embryos and that this mechanism may play a pivotal role during early embryonic development.
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Lidbury, Brett A., Badia Kita, Alice M. Richardson, Donald P. Lewis, Edwina Privitera, Susan Hayward, David de Kretser, and Mark Hedger. "Rethinking ME/CFS Diagnostic Reference Intervals via Machine Learning, and the Utility of Activin B for Defining Symptom Severity." Diagnostics 9, no. 3 (July 19, 2019): 79. http://dx.doi.org/10.3390/diagnostics9030079.
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Biomarker discovery applied to myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), a disabling disease of inconclusive aetiology, has identified several cytokines to potentially fulfil a role as a quantitative blood/serum marker for laboratory diagnosis, with activin B a recent addition. We explored further the potential of serum activin B as a ME/CFS biomarker, alone and in combination with a range of routine test results obtained from pathology laboratories. Previous pilot study results showed that activin B was significantly elevated for the ME/CFS participants compared to healthy (control) participants. All the participants were recruited via CFS Discovery and assessed via the Canadian/International Consensus Criteria. A significant difference for serum activin B was also detected for ME/CFS and control cohorts recruited for this study, but median levels were significantly lower for the ME/CFS cohort. Random Forest (RF) modelling identified five routine pathology blood test markers that collectively predicted ME/CFS at ≥62% when compared via weighted standing time (WST) severity classes. A closer analysis revealed that the inclusion of activin B to the panel of pathology markers improved the prediction of mild to moderate ME/CFS cases. Applying correct WST class prediction from RFA modelling, new reference intervals were calculated for activin B and associated pathology markers, where 24-h urinary creatinine clearance, serum urea and serum activin B showed the best potential as diagnostic markers. While the serum activin B results remained statistically significant for the new participant cohorts, activin B was found to also have utility in enhancing the prediction of symptom severity, as represented by WST class.
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Takeda, Masaya, Fumio Otsuka, Hiroyuki Otani, Kenichi Inagaki, Tomoko Miyoshi, Jiro Suzuki, Yukari Mimura, Toshio Ogura, and Hirofumi Makino. "Effects of peroxisome proliferator-activated receptor activation on gonadotropin transcription and cell mitosis induced by bone morphogenetic proteins in mouse gonadotrope LβT2 cells." Journal of Endocrinology 194, no. 1 (July 2007): 87–99. http://dx.doi.org/10.1677/joe-07-0138.
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Involvement of peroxisome proliferator-activated receptor-γ (PPAR-γ ) activation and bone morphogenetic protein (BMP) signaling in regulating cell proliferation and hormonal production of pituitary tumors has been reported, although the underlying mechanism remains poorly understood. Here, we investigated regulatory roles of PPARα and PPARγ in gonadotropin transcription and cell mitosis modulated by pituitary activin/BMP systems using a mouse gonadotropinoma cell line Lβ T2, which expresses activin/BMP receptors, transcription factor Smads, PPARα , and PPARγ . In Lβ T2 cells, BMP signaling shown by Smad1/5/8 phosphorylation and Id-1 transcription was readily activated by BMPs. A PPARγ agonist, pioglitazone significantly reduced BMP-induced DNA synthesis by Lβ T2; whereas the PPARα agonist, fenofibric acid, did not. In accordance with the effects on cell mitosis, pioglitazone but not fenofibric acid significantly decreased BMP-induced Id-1-Luc activation. Neither fenofibric acid nor pioglitazone affected activin signaling detected by (CAGA)9-Luc activity. Both PPARα and PPARγ ligands directly suppressed transcriptional activities of FSHβ , LHβ , and GnRHR. Activation of PPARα and PPARγ increased mRNA levels of follistatin, but did not affect the expression of follistatin-related gene. Thus, PPAR agonists not only directly suppress gonadotropin transcription and BMP signaling, but also inhibit the biological actions of activins which facilitate gonadotropin transcription through upregulating follistatin expression. In addition, pioglitazone increased BMP ligands mRNA, but decreased activin-β B mRNA in Lβ T2 cells. Collectively, PPAR activation differentially regulates gonadotrope cell proliferation and gonadotropin transcription in a ligand-dependent manner.
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Munro, Iain. "An interview with Chelsea Manning’s lawyer: Nancy Hollander on human rights and the protection of whistleblowers." Organization 26, no. 2 (June 13, 2018): 276–90. http://dx.doi.org/10.1177/1350508418779648.
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This article presents an edited interview with Nancy Hollander, a prominent human rights activist and criminal defense lawyer. The primary focus of the interview is Ms Hollander’s work as the lead defense counsel for the whistleblower, Chelsea Manning. The main themes addressed in the interview are (a) the close links between the practice of whistleblowing and human rights activism, (b) the fact that whistleblowers are not only subject to retaliation but are also being increasingly criminalized, and (c) the creation of a broad support network for whistleblowers like Chelsea Manning.
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Okuma, Y., A. E. O’Connor, J. A. Muir, P. G. Stanton, D. M. de Kretser, and M. P. Hedger. "Regulation of activin A and inhibin B secretion by inflammatory mediators in adult rat Sertoli cell cultures." Journal of Endocrinology 187, no. 1 (October 2005): 125–34. http://dx.doi.org/10.1677/joe.1.06266.
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The regulation of Sertoli cell activin A and inhibin B secretion during inflammation was investigated in vitro. Adult rat Sertoli cells were incubated with the inflammatory mediators, lipopolysaccharide (LPS), interleukin-1β (IL-1β), IL-6 and the IL-1 receptor antagonist (IL-1ra) over 48 h in culture. Activin A, inhibin B and IL-1α were measured in the culture medium by specific two-site ELISAs. Both IL-1β- and LPS-stimulated activin A and inhibited inhibin B secretion. LPS also stimulated the production of IL-1α in the cultures. In contrast to IL-1β, IL-6 had no effect on activin A, although it did have a significant inhibitory effect on inhibin B secretion. Ovine follicle-stimulating hormone (FSH) and the cAMP analogue dibutyryl cAMP opposed the actions of IL-1 and LPS by suppressing activin A and IL-1α secretion and by stimulating inhibin B. Blocking IL-1 activity in the cultures by addition of an excess of IL-1ra completely prevented the response of activin A to exogenous IL-1β, and reduced the response to LPS by 50%. In the presence of IL-1ra, basal secretion of inhibin B was increased, but IL-1ra was unable to reverse the suppression of inhibin B by LPS. These data indicate the importance of both IL-1 isoforms in regulating secretion of activin A and inhibin B by mature Sertoli cells during inflammation. The data also establish that inflammation exerts its effects on activin A and inhibin B secretion via other pathways in addition to those mediated by IL-1, and that hormonal stimulation by FSH and cAMP moderates the Sertoli cell response to inflammation. Interference with the complex interactions between these cytokines and hormones may contribute to the disruption of reproductive function that can accompany infection and illness in men.
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Galimova, E. F., G. Kh Akhmadullina, K. V. Bulygin, K. S. Mochalov, and Sh N. Galimov. "Inhibin B and activin A in the pathogenesis of idiopathic male infertility." Kazan medical journal 96, no. 5 (October 15, 2015): 749–52. http://dx.doi.org/10.17750/kmj2015-749.
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Aim. To assess the role of serum and ejaculate inhibin-activin status disorders in the development of reproductive disorders at idiopathic male infertility.
Methods. The research includes data of laboratory and clinical examination of 82 infertile and 60 fertile men. Serum and semen levels of reproduction regulatory peptides inhibin B and activin A were determined using standard commercially available kits for enzyme-linked immunosorbent assay. Other parameters of ejaculate were also investigated.
Results. In men with infertility of the unknown cause, sperm cell concentration was significantly decreased, and the proportion of sex cells with morphological anomalies was increased. The main features of inhibin-activin profile of biological fluids in healthy males with proven fertility were revealed, which were the significant gradient of inhibin and activin intertissue concentrations and domination of these molecular fertility factors in seminal plasma, corresponding with the views of their key role in sperm fertilizing capacity. In patients with pathospermia, the significant decrease of inhibin B concentration in the ejaculate but not in serum, associated with increased activin A levels was revealed, accompanied by characteristic shift of inhibin-activin ratio associated with the deterioration of quality and quantity parameters of semen.
Conclusion. Revealed changes in the inhibin-activin sperm plasma mirror may be a pathogenetic basis for the idiopathic infertility in couples. Inhibin-activin coefficient in blood serum and seminal fluid may be used as a promising diagnostic and prognostic marker of reproductive dysfunction risk.
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Kitamura, Kenichiro, Naoki Shiraishi, William D. Singer, Mary E. Handlogten, Kimio Tomita, and R. Tyler Miller. "Endothelin-B receptors activate Gα13." American Journal of Physiology-Cell Physiology 276, no. 4 (April 1, 1999): C930—C937. http://dx.doi.org/10.1152/ajpcell.1999.276.4.c930.
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Endothelin (ET) receptors activate heterotrimeric G proteins that are members of the Gi, Gq, and Gs families but may also activate members of other families such as Gα12/13. Gα13 has multiple complex cellular effects that are similar to those of ET. We studied the ability of ET receptors to activate Gα13 using an assay for G protein α-chain activation that is based on the fact that an activated (GTP-bound) α-chain is resistant to trypsinization compared with an inactive (GDP-bound) α-chain. Nonhydrolyzable guanine nucleotides and AlMgF protected Gα13 from degradation by trypsin. In membranes from human embryonic kidney 293 cells that coexpress ETB receptors and α13, ET-3 and 5′-guanylylimidodiphosphate [Gpp(NH)p] increased the protection of α13 compared with Gpp(NH)p alone. The specificity of ETBreceptor-α13 coupling was documented by showing that β2receptors and isoproterenol or ETAreceptors and ET-1 did not activate α13 and that a specific antagonist for ETB receptors blocked ET-3-dependent activation of α13.
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Woodruff, T. K., P. Sluss, E. Wang, I. Janssen, and M. S. Mersol-Barg. "Activin A and follistatin are dynamically regulated during human pregnancy." Journal of Endocrinology 152, no. 2 (February 1997): 167–74. http://dx.doi.org/10.1677/joe.0.1520167.
Full textAbstract:
Abstract Activin A (βA–βA) and activin B (βB–βB) are related dimeric proteins that regulate numerous cellular activities. Activin activity is bioneutralized by follistatin, a specific and high-affinity binding protein. Recently, our group developed specific and sensitive enzyme-linked immunosorbent activin assays that do not detect either activin isoform when bound to follistatin, therefore, the assays are specific for biologically relevant ligands. Activin A is measurable in the serum of pregnant women (cross-sectional sample collection), while activin B is not detected in maternal serum. However, activin B is measurable in amniotic fluid and cord blood sera. The purpose of this study was to measure serum activin A, activin B, and follistatin prospectively in longitudinally collected samples during pregnancy. This study design offered observations of relative changes in serum hormone concentration with each person serving as an internal reference. Serum samples were collected bimonthly from seven pregnant women beginning within the second month of gestation, and up to, but not including, the onset of labor. Six of the seven women had normal labor and delivery. One patient required pitocin (an oxytocin agonist) for induction of labor which led to delivery. Activin A, activin B, total follistatin, free follistatin, human chorionic gonadotropin, estradiol, progesterone, FSH, and LH were measured in maternal serum samples using specific assays. Serum activin A levels increased in the final month of pregnancy in the six patients who delivered following normal labor (<0·78 ng/ml (first trimester) to 1–6 ng/ml (term)). Activin B was not detected in any serum sample (<0·78 pg/ml). Total serum follistatin (free follistatin, follistatin–activin, and follistatin–inhibin) increased 10- to 45-fold in the final month of pregnancy in four of the women undergoing normal labor (10 ng/ml (first trimester) to 100–450 ng/ml (final month)). Total follistatin was high and variable in two women throughout pregnancy. Total follistatin returned to basal serum concentration in three of the patients during the last 2 weeks of pregnancy. Free follistatin was detected throughout pregnancy (range <2–35 ng/ml). Free follistatin represented a small percentage of the total follistatin throughout the time of pregnancy and did not rise coincident with the rise in total follistatin. Serum activin A and activin B were not detected during the entire course of pregnancy in the one patient who did not have normal labor and total follistatin did not rise in the last trimester of pregnancy. Gonadotropin and steroid hormones were measured in all patients and were within normative ranges for human pregnancy (inclusive of the non-laboring patient). The results suggest that immunodetectable activin A is present in the third trimester of pregnant women who have normal onset labor. The total follistatin assay results suggest that follistatin–activin (or –inhibin) complexes are upregulated during the third trimester of pregnancy. Importantly, activin A production exceeds the binding capacity of circulating follistatin. Because binding protein free activin A is biologically active we conclude that the activin A detected in late pregnancy is biologically relevant. The findings are consistent with our hypothesis that activin A is an endocrine factor during the last trimester of human pregnancy and may be involved in normal labor. Journal of Endocrinology (1997) 152, 167–174
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Besson-Fournier, Céline, Chloé Latour, Léon Kautz, Jessica Bertrand, Tomas Ganz, Marie-Paule Roth, and Hélène Coppin. "Induction of activin B by inflammatory stimuli up-regulates expression of the iron-regulatory peptide hepcidin through Smad1/5/8 signaling." Blood 120, no. 2 (July 12, 2012): 431–39. http://dx.doi.org/10.1182/blood-2012-02-411470.
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Abstract Anemia is very common in patients suffering from infections or chronic inflammation and can add substantially to the morbidity of the underlying disease. It is mediated by excessive production of the iron-regulatory peptide hepcidin, but the signaling pathway responsible for hepcidin up-regulation in the inflammatory context is still not understood completely. In the present study, we show that activin B has an unexpected but crucial role in the induction of hepcidin by inflammation. There is a dramatic induction of Inhbb mRNA, encoding the activin βB-subunit, in the livers of mice challenged with lipopolysaccharide, slightly preceding an increase in Smad1/5/8 phosphorylation and Hamp mRNA. Activin B also induces Smad1/5/8 phosphorylation in human hepatoma–derived cells and, synergistically with IL-6 and STAT-3 signaling, up-regulates hepcidin expression markedly, an observation confirmed in mouse primary hepatocytes. Pretreatment with a bone morphogenic protein type I receptor inhibitor showed that the effect of activin B on hepcidin expression is entirely attributable to its effect on bone morphogenetic protein signaling, most likely via activin receptor-like kinase 3. Activin B is therefore a novel and specific target for the treatment of anemia of inflammation.
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Shi, Feng-Tao, Anthony P. Cheung, He-Feng Huang, and Peter C. K. Leung. "Effects of Endogenous Growth Differentiation Factor 9 on Activin A-Induced Inhibin B Production in Human Granulosa-Lutein Cells." Journal of Clinical Endocrinology & Metabolism 94, no. 12 (December 1, 2009): 5108–16. http://dx.doi.org/10.1210/jc.2009-1047.
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Background: We recently reported on the effects of exogenous growth differentiation factor 9 (GDF9) in enhancing activin A-induced inhibin βB-subunit mRNA and inhibin B levels in human granulosa-lutein (hGL) cells by modulating key components of the activin signaling pathway. We undertook the following study to characterize the role of endogenous GDF9 in this regard. Methods: We compared inhibin subunit (α, βA, and βB) mRNA and inhibin B levels and activation of activin receptors (ACVRs) and Smad signaling pathway in hGL cells obtained from women undergoing in vitro fertilization and cultured with and without activin A treatment after GDF9-targeting small interfering RNA transfection. GDF9, inhibin subunits, ACVR2B/1B and Smad2/3/4/7 mRNA and/or protein levels, Smad phosphorylation, and inhibin B were assessed with RT-PCR, immunoblotting, and ELISA. Data were analyzed by ANOVA followed by Tukey’s test. Results: GDF9 was detected as mRNA and protein in hGL cells and protein in follicular fluid from all 11 patients tested. Reduced endogenous GDF9 expression after targeting small interfering RNA transfection was associated with decreased ACVR2B/1B and Smad2/3/4 but increased inhibitory Smad7 mRNA and protein levels and, consequently, reduced activin A-induced βB-subunit mRNA and inhibin B levels. Conclusions: We report here for the first time autocrine roles for endogenous GDF9 in hGL cells in enhancing activin A-induced βB-subunit mRNA and inhibin B levels via key components of the activin signaling pathway. However, the relative contributions of GDF9 in granulosa cells vs. oocyte as autocrine/paracrine regulators of βB-subunit and inhibin B production in normal and abnormal human ovarian functions remain to be determined.
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Shi, Feng-Tao, Anthony P. Cheung, He-Feng Huang, and Peter C. K. Leung. "Effects of Endogenous Growth Differentiation Factor 9 on Activin A-Induced Inhibin B Production in Human Granulosa-Lutein Cells." Molecular Endocrinology 23, no. 11 (November 1, 2009): 1936. http://dx.doi.org/10.1210/mend.23.11.9995.
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ABSTRACT Background We recently reported on the effects of exogenous growth differentiation factor 9 (GDF9) in enhancing activin A-induced inhibin βB-subunit mRNA and inhibin B levels in human granulosa-lutein (hGL) cells by modulating key components of the activin signaling pathway. We undertook the following study to characterize the role of endogenous GDF9 in this regard. Methods We compared inhibin subunit (α, βA, and βB) mRNA and inhibin B levels and activation of activin receptors (ACVRs) and Smad signaling pathway in hGL cells obtained from women undergoing in vitro fertilization and cultured with and without activin A treatment after GDF9-targeting small interfering RNA transfection. GDF9, inhibin subunits, ACVR2B/1B and Smad2/3/4/7 mRNA and/or protein levels, Smad phosphorylation, and inhibin B were assessed with RT-PCR, immunoblotting, and ELISA. Data were analyzed by ANOVA followed by Tukey’s test. Results GDF9 was detected as mRNA and protein in hGL cells and protein in follicular fluid from all 11 patients tested. Reduced endogenous GDF9 expression after targeting small interfering RNA transfection was associated with decreased ACVR2B/1B and Smad2/3/4 but increased inhibitory Smad7 mRNA and protein levels and, consequently, reduced activin A-induced βB-subunit mRNA and inhibin B levels. Conclusions We report here for the first time autocrine roles for endogenous GDF9 in hGL cells in enhancing activin A-induced βB-subunit mRNA and inhibin B levels via key components of the activin signaling pathway. However, the relative contributions of GDF9 in granulosa cells vs. oocyte as autocrine/paracrine regulators of βB-subunit and inhibin B production in normal and abnormal human ovarian functions remain to be determined.
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Besson-Fournier, Celine, Aurelie Gineste, Chloe Latour, Ophelie Gourbeyre, Delphine Meynard, Patricia Aguilar-Martinez, Eric Oswald, Patricia Martin, Helene Coppin, and Marie-Paule Roth. "Hepcidin Upregulation By Inflammation Is Not Causally Related to Liver Activation of Smad1/5/8 Signaling By Activin B." Blood 128, no. 22 (December 2, 2016): 262. http://dx.doi.org/10.1182/blood.v128.22.262.262.
Full textAbstract:
Abstract Hepcidin induction during inflammation is partly due to direct transcriptional regulation by the IL6/STAT3 pathway. However, SMAD1/5/8 signaling is also believed to have a role in hepcidin regulation during inflammation, as inhibitors of BMP type I receptors or the BMP ligand antagonist ALK3-Fc block hepcidin induction, increase iron availability, and ameliorate anemia in different animal models of inflammation. We previously observed that LPS stimulates liver Smad1/5/8 signaling even in Bmp6-deficient mice and our data suggested that, rather than Bmp6, activin B could be the activating ligand of this pathway during inflammation. There was indeed a dramatic induction of Inhbb mRNA, encoding activin B, in the liver of mice challenged with LPS, slightly preceding an increase in Smad1/5/8 phosphorylation and hepcidin (Hamp) mRNA. In liver cells in vitro, activin B stimulated not only canonical Smad2/3 but also non-canonical Smad1/5/8 signaling and hepcidin expression. Finally, pretreatment with a BMP type I receptor inhibitor showed that the effect of activin B on hepcidin expression in liver cells was entirely attributable to its effect on non-canonical Smad1/5/8 signaling. However, although these data demonstrate that activin B potently crossactivates non-canonical Smad1/5/8 signaling to induce hepcidin expression in hepatocytes in vitro, they do not definitively prove the role of activin B in hepcidin induction in vivo. Therefore, the goal of the present study was to challenge Inhbb-/- mice (deficient in activin B) with LPS or infect them with E. Coli and examine whether, as expected from the in vitro data, the lack of activin B prevents stimulation of both canonical Smad2/3 and non-canonical Smad1/5/8 signaling and induction of hepcidin in these mice. We first showed that activin B is actually the ligand that in vivo induces hepatic Smad2/3 and Smad1/5/8 phosphorylation in response to inflammatory stimuli such as LPS and bacterial infections. Indeed, these signaling pathways are no longer activated in Inhbb-/- mice (Fig. 1A). Interestingly however, we found that the lack of activin B and, as a consequence, the lack of activation of Smad1/5/8 signaling does not impair the induction of hepatic hepcidin expression by these inflammatory stimuli (Fig. 1B), illustrating the limitations of in vitro studies in simulating what is actually going on inside a liver. In conclusion, although activin B is directly responsible for liver activation of Smad1/5/8 signaling in vivo, this signaling pathway is not governing upregulation of hepcidin production in animals submitted to inflammatory stimuli. We also noticed that the level of Smad1/5/8 phosphorylation in the liver of mice challenged with LPS is not correlated with the expression of hepcidin. Indeed, although LPS-treated Bmp6-/- and wild-type mice have similar activation of Smad1/5/8 (Fig. 2A), the amount of circulating hepcidin in Bmp6-/- mice is about three times lower than in wild-type mice (Fig. 2B). This could indicate that induction of Smad1/5/8 signaling by inflammatory stimuli takes place in non-parenchymal cells rather than in hepatocytes and has no impact on hepcidin expression. Further investigations are necessary to determine in which liver cells activin B activates the canonical Smad2/3 and non-canonical Smad1/5/8 signaling observed in this study, and what are the exact target genes induced by this signaling. Disclosures No relevant conflicts of interest to declare.