Mus musculus
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ABSTRACT:
PROVIDER: PRJNA382543 | ENA |
REPOSITORIES: ENA
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Project description:The effects of doxorubicin and blocking activin receptor 2B ligands in mice [muscle]
| PRJNA311341 | ENA
Project description:The effects of doxorubicin and blocking activin receptor 2B ligands in mice
| PRJNA382541 | ENA
Project description:Doxorubicin is a widely used and effective anthracycline chemotherapy drug. However, it causes cardiotoxicity and also a few negative effects on skeletal muscle as well. As a result, cancer treatment might actually worsen cancer-induced cachexia and consequently the prognosis of the disease. Inhibiting myostatin/activin signaling is known to increase muscle size. This pathway blockade by soluble activin receptor IIB (sAcvR2B-Fc) has also prolonged survival in cancer, even of animals in which tumor growth is not inhibited. It is not known, however, whether blocking this pathway affects chemotherapy-induced muscle wasting. We found that doxorubicin induces muscle atrophy which is prevented by a blocker for activin receptor 2B ligands (sAcvR2B-Fc)
2017-12-04 | GSE97642 | GEO
Project description:Doxorubicin is a widely used and effective anthracycline chemotherapy drug. However, it causes cardiotoxicity and also a few negative effects on skeletal muscle as well. As a result, cancer treatment might actually worsen cancer-induced cachexia and consequently the prognosis of the disease. Inhibiting myostatin/activin signaling is known to increase muscle size. This pathway blockade by soluble activin receptor IIB (sAcvR2B-Fc) has also prolonged survival in cancer, even of animals in which tumor growth is not inhibited. It is not known, however, whether blocking this pathway affects chemotherapy-induced muscle wasting. We found that doxorubicin induces muscle atrophy which is prevented by a blocker for activin receptor 2B ligands (sAcvR2B-Fc).
2016-09-25 | GSE77745 | GEO
Project description:This study was to compare the gene expression of our anti-GDF8 (i.e. anti-myostatin) and anti-activin A antibody combination to that of the activin receptor type IIB (ActRIIB.hFc) trap in SCID mice. The study was conducted in tibialis anterior muscle that is a common muscle type for the hypertrophy study. The combination treatment produces very similar muscle growth in tibialis muscle as the ActRIIB.hFc trap, however our combination blocks two specific ligands compared to the many ligands the receptor trap will inhibit. The difference in gene expression between these groups demonstrates that despite producing similar muscle growth, the trap affecting more genes in muscle without producing additional muscle hypertrophy.
2017-06-01 | E-MTAB-4943 | biostudies-arrayexpress
Project description:Cardiovascular disease is the prevailing cause of death among cancer survivors. Remarkable increase in cardiac disease burden in this group is likely due to the effects of cancer itself and, especially, cardiotoxic cancer treatments. Of the cardiotoxic cancer treatments, anthracyclines are notoriously known for causing vascular damage and severe cardiovascular complications. A defining feature of cardiac damage by doxorubicin (Dox), a prototypical anthracycline, is that it typically progresses after completion of chemotherapy. As the nature of delayed deterioration is not understood we focused in this study on the events that occur upon completion of chemotherapy. We adopted the Dox treatment/washout model to examine its lasting effects on endothelial cells. Our ChIP sequencing, transcriptomic, reporter plasmid, and Smad2/3 phosphorylation experiments demonstrated the enhanced activity of the canonical TGF-b/activin pathway during Dox washout. Another notable feature was sustained mesenchymal reprogramming with significant upregulation of transcripts characteristic of fibroblastic and smooth muscle lineages. We utilized a selective ALK4/5/7 receptor kinase inhibitor, SB431542 (SB), to probe the role of the canonical TGF-/activin pathways in endothelial-to-mesenchymal reprogramming by Dox. When present during Dox washout, SB blocked increased expression of both mesenchymal transcripts and protein markers, and prevented cytoskeletal changes and fibronectin production by the treated endothelial cells. Cytoskeletal rearrangements led to increased endothelial monolayer permeability that was abolished by SB treatment. Thus, increased production of ALK4/5 receptor ligands, TGF-2 and activin, and heightened Smad2/3 activation response to these ligands during Dox washout leads to sustained mesenchymal reprogramming of endothelial cells and compromised endothelial barrier function.
2025-06-26 | GSE300789 | GEO
Project description:Cardiovascular disease is the prevailing cause of death among cancer survivors. Remarkable increase in cardiac disease burden in this group is likely due to the effects of cancer itself and, especially, cardiotoxic cancer treatments. Of the cardiotoxic cancer treatments, anthracyclines are notoriously known for causing vascular damage and severe cardiovascular complications. A defining feature of cardiac damage by doxorubicin (Dox), a prototypical anthracycline, is that it typically progresses after completion of chemotherapy. As the nature of delayed deterioration is not understood we focused in this study on the events that occur upon completion of chemotherapy. We adopted the Dox treatment/washout model to examine its lasting effects on endothelial cells. Our ChIP sequencing, transcriptomic, reporter plasmid, and Smad2/3 phosphorylation experiments demonstrated the enhanced activity of the canonical TGF-beta/activin pathway during Dox washout. Another notable feature was sustained mesenchymal reprogramming with significant upregulation of transcripts characteristic of fibroblastic and smooth muscle lineages. We utilized a selective ALK4/5/7 receptor kinase inhibitor, SB431542 (SB), to probe the role of the canonical TGF-beta/activin pathways in endothelial-to-mesenchymal reprogramming by Dox. When present during Dox washout, SB blocked increased expression of both mesenchymal transcripts and protein markers, and prevented cytoskeletal changes and fibronectin production by the treated endothelial cells. Cytoskeletal rearrangements led to increased endothelial monolayer permeability that was abolished by SB treatment. Thus, increased production of ALK4/5 receptor ligands, TGF-beta2 and activin, and heightened Smad2/3 activation response to these ligands during Dox washout leads to sustained mesenchymal reprogramming of endothelial cells and compromised endothelial barrier function.
2025-06-26 | GSE300800 | GEO
Project description:TGFβ/Activin subfamilies of ligands. In Drosophila the TGFβ/Activin branch includes three ligands, Myoglianin (Myo), Activin-β (Actβ) and Dawdle (Daw). All three ligands signal through the same type I receptor, Baboon, in conjunction with a type II receptor, Punt or Wit. Baboon has three distinct splice isoforms, termed Babo A, Babo B and Babo C, that differ only in exon 4, which encodes the ligand binding domain. This difference enables each ligand to potentially signal through a single splice isoform39. Formation of the ligand receptor complex stimulates phosphorylation of the receptor-Smad, dSmad2/Smox, which translocates to the nucleus as a complex with the co-Smad Medea where it serves as a transcriptional transducer. In order to gain insight into the genes regulated by Actβ we carried out a transcriptomic analysis comparing Actβ mutants to wild-type controls.
2024-06-28 | GSE270911 | GEO
Project description:Th17 cells are known to exert pathogenic and non-pathogenic functions. Although the cytokine transforming growth factor β1 (TGF-β1) is instrumental for Th17 cell differentiation, it is dispensable for generation of pathogenic Th17 cells. Here, we examined the T cell-intrinsic role of Activin-A, a TGF-β superfamily member closely related to TGF-β1, in pathogenic Th17 cell differentiation. Activin-A expression was increased in individuals with relapsing-remitting multiple sclerosis and in mice with experimental autoimmune encephalomyelitis. Stimulation with interleukin-6 and Activin-A induced a molecular program that mirrored that of pathogenic Th17 cells and was inhibited by blocking Activin-A signaling. Genetic disruption of Activin-A and its receptor ALK4 in T cells impaired pathogenic Th17 cell differentiation in vitro and in vivo. Mechanistically, extracellular-signal-regulated kinase (ERK) phosphorylation, which was essential for pathogenic Th17 cell differentiation, was suppressed by TGF-β1-ALK5 but not Activin-A-ALK4 signaling. Thus, Activin-A drives pathogenic Th17 cell differentiation, implicating the Activin-A-ALK4-ERK axis as a therapeutic target for Th17 cell-related diseases.
2021-01-11 | GSE151533 | GEO
Project description:Phosphorylation of Smad3 is a critical mediator of TGF-b signaling, which plays an important role in regulating innate immune responses. However, whether Smad3 activation can be regulated in innate immune cells in TGF-β-independent contexts remains unknown. Here, we show that Smad3 is activated through the phosphorylation of its C-terminal residues (pSmad3C) in murine and human macrophages in response to bacterial and viral antigens, which is mediated by Activin A in a TGF-b independent manner. Specifically, infectious ligands, such as LPS, induced secretion of Activin A through the transcription factor STAT5 in macrophages, and Activin A signaling in turn activated pSmad3C. This Activin A-Smad3 axis controlled the mitochondrial ATP production and ATP conversion into adenosine by CD73 in macrophages, enforcing an anti-inflammatory mechanism. Consequently, mice with a deletion of Activin A receptor 1b specifically in macrophages (Acvr1bf/f-Lyz2cre) succumbed more to sepsis due to uncontrolled inflammation and exhibited exacerbated skin disease in a mouse model of imiquimod-induced psoriasis. Thus, we have revealed a previously unrecognized natural brake to inflammation in macrophages that occurs through the activation of Smad3 in an Activin A-dependent manner.
2025-05-07 | GSE284154 | GEO