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Cell Death & Disease Mar 2022Circular RNAs (circRNAs) play vital regulatory roles in the progression of multiple cancers. In our study, transcriptome analysis and self-organizing maps (SOM) were...
Circular RNAs (circRNAs) play vital regulatory roles in the progression of multiple cancers. In our study, transcriptome analysis and self-organizing maps (SOM) were applied to screen backbone circRNAs in gastric cancer (GC). Upon validation of the expression patterns of screened circRNAs, gain- and loss-of-function assays were performed in vitro and in vivo. Underlying mechanisms were investigated using RNA pull-down, luciferase reporter assay and RNA immunoprecipitation. The expression of circTHBS1 was significantly increased in GC and associated with poor prognosis. CircTHBS1 facilitated the malignant behavior and epithelial-to-mesenchymal transition of GC cells. Mechanistically, circTHBS1 sponged miR-204-5p to promote the expression of Inhibin Subunit Beta A (INHBA). Moreover, circTHBS1 could enhance the HuR-mediated mRNA stability of INHBA, which subsequently activated the TGF-β pathway. Our research identified circTHBS1 as an oncogenic circRNA that enhances GC malignancy by elevating INHBA expression, providing new insight and a feasible target for the diagnosis and treatment of GC.
Topics: Cell Line, Tumor; Cell Proliferation; Gene Expression Regulation, Neoplastic; Humans; Inhibin-beta Subunits; MicroRNAs; RNA, Circular; RNA, Messenger; Stomach Neoplasms; Thrombospondin 1
PubMed: 35338119
DOI: 10.1038/s41419-022-04720-0 -
Methods in Molecular Biology (Clifton,... 2022Different states of pluripotency can be captured in vitro depending on the embryo stage from which they are derived and the culture conditions. Pluripotency is a...
Different states of pluripotency can be captured in vitro depending on the embryo stage from which they are derived and the culture conditions. Pluripotency is a continuum of different states between the two extremes of naïve embryonic stem cells (ESCs) and primed Epiblast Stem Cells (EpiSCs), which resemble the pre/peri- and post- implantation embryo, respectively. The transition from naïve to primed pluripotency can be induced by growing naïve ESCs in EpiSCs medium, containing bFGF and Activin. Here we report the detailed protocol to generate and characterize the epiblast-like cells (EpiLCs), which correspond to a primed intermediate state between naïve ESCs and EpiSCs.
Topics: Activins; Cells, Cultured; Embryonic Stem Cells; Germ Layers; Pluripotent Stem Cells
PubMed: 35486236
DOI: 10.1007/978-1-0716-2281-0_3 -
Drugs of Today (Barcelona, Spain : 1998) Jul 2020Recently, after years of research often characterized by disappointments and frustrations, finally a new drug impacting on pathological human erythropoiesis has been... (Review)
Review
Recently, after years of research often characterized by disappointments and frustrations, finally a new drug impacting on pathological human erythropoiesis has been developed and approved. This drug, luspatercept-aamt (Reblozyl), proved to be effective in both malignant and nonmalignant disease characterized by ineffective erythropoiesis with consequent life-threatening severe anemia. Moreover, for the first time, a medication demonstrated efficacy and effectiveness in β-thalassemia where no other drug, including recombinant human erythropoietin, showed effectiveness in improving anemia. Despite recent impressive advances in understanding human normal and abnormal erythropoiesis, there are few new drugs and limited pharma research focusing on ineffective erythropoiesis. This review will discuss recent advances in understanding normal and pathological erythropoiesis that represent the background to discuss pharmacology, toxicology, efficacy, safety and effectiveness of this new drug for the treatment of human β-thalassemia.
Topics: Activin Receptors, Type II; Activins; Humans; Immunoglobulin Fc Fragments; Recombinant Fusion Proteins; beta-Thalassemia
PubMed: 32648855
DOI: 10.1358/dot.2020.56.7.3159184 -
Placenta May 2023Activin A is a two-subunit protein belonging to the transforming growth factor β superfamily. First discovered almost three decades ago, it has since been implicated in... (Review)
Review
Activin A is a two-subunit protein belonging to the transforming growth factor β superfamily. First discovered almost three decades ago, it has since been implicated in diverse physiological roles, ranging from wound repair to reproduction. After 30 years of research, altered activin A levels are now understood to be associated with the development of various diseases, making activin A a potential therapeutic target. In pregnancy, the placenta and fetal membranes are major producers of activin A, with significantly enhanced serum concentrations now recognised as a contributor to numerous gestational disorders. Evidence now suggests that circulating levels of activin A may be clinically relevant in the early detection of pregnancy complications, including miscarriage and preeclampsia. This review aims to summarise our current understanding of activin A as a potential diagnostic marker in common pregnancy pathologies.
Topics: Pregnancy; Female; Humans; Inhibins; Activins; Reproduction; Pregnancy Complications
PubMed: 37028223
DOI: 10.1016/j.placenta.2023.03.008 -
Current Opinion in Rheumatology Jul 2019Patients with chronic kidney disease have a high risk of fractures and no established treatments that have been shown to prevent the bone disease. The physiology of... (Review)
Review
PURPOSE OF REVIEW
Patients with chronic kidney disease have a high risk of fractures and no established treatments that have been shown to prevent the bone disease. The physiology of renal osteodystrophy is complex and recently more factors have been found that complicate the mineral metabolism. The recognition that vascular calcifications are related to bone disease has made treatment even more challenging.
RECENT FINDINGS
The most exciting new findings relate to the signaling pathways that are seen in kidney disease and how they cause abnormalities in bone physiology. In particular, wnt and activin signaling pathways are seen early in the course of renal disease. The bones react by increasing FGF-23, which targets both renal phosphate secretion and a variety of other systemic effects. Secreted klotho is another newly described hormone with effects on several systems.Clinical studies have focused on treatments for hyperparathyroidism and phosphate, and frustrating limitations of the treatments used for ordinary osteoporosis.
SUMMARY
Treatment of bone disease in patients with chronic kidney disease is challenging, and understanding the physiological pathways could lead to novel therapies.
Topics: Activins; Bone and Bones; Chronic Kidney Disease-Mineral and Bone Disorder; Disease Progression; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Humans; Renal Insufficiency, Chronic; Wnt Proteins
PubMed: 31135568
DOI: 10.1097/BOR.0000000000000626 -
Biomedicine & Pharmacotherapy =... Sep 2023Sotatercept (ACE-011) is an activin receptor IIA-Fc (ActRIIA-Fc) fusion protein currently under investigation for its potential in the treatment of hematologic diseases.... (Review)
Review
Sotatercept (ACE-011) is an activin receptor IIA-Fc (ActRIIA-Fc) fusion protein currently under investigation for its potential in the treatment of hematologic diseases. By impeding the activities of the overexpressed growth and differentiation factor 11 (GDF11), activin A, and other members of the transforming growth factor-β (TGF-β) superfamily, commonly found in hematologic disorders, sotatercept aims to restore the normal functioning of red blood cell maturation and osteoblast differentiation. This action is anticipated to enhance anemia management and hinder the progression of myeloma. Simultaneously, comprehensive research is ongoing to investigate sotatercept's pharmacokinetics and potential adverse reactions, thus laying a robust foundation for its prospective clinical use. In this review, we provide a detailed overview of TGF-β pathways in physiological and hematologic disorder contexts, outline the potential mechanism of sotatercept, and delve into its pharmacokinetics and clinical research advancements in various hematologic diseases. A particular emphasis is given to the relationship between sotatercept dosage and its efficacy or associated adverse reactions.
Topics: Humans; Prospective Studies; Anemia; Erythropoiesis; Recombinant Fusion Proteins; Transforming Growth Factor beta; Activins; Bone Morphogenetic Proteins; Growth Differentiation Factors
PubMed: 37516019
DOI: 10.1016/j.biopha.2023.115239 -
Experimental Biology and Medicine... Feb 2021Heparin and heparan sulfate (HS) are highly sulfated polysaccharides covalently bound to cell surface proteins, which directly interact with many extracellular proteins,...
Heparin and heparan sulfate (HS) are highly sulfated polysaccharides covalently bound to cell surface proteins, which directly interact with many extracellular proteins, including the transforming growth factor-β (TGFβ) family ligand antagonist, follistatin 288 (FS288). Follistatin neutralizes the TGFβ ligands, myostatin and activin A, by forming a nearly irreversible non-signaling complex by surrounding the ligand and preventing interaction with TGFβ receptors. The FS288-ligand complex has higher affinity than unbound FS288 for heparin/HS, which accelerates ligand internalization and lysosomal degradation; however, limited information is available for how FS288 interactions with heparin affect ligand binding. Using surface plasmon resonance (SPR) we show that preincubation of FS288 with heparin/HS significantly decreased the association kinetics for both myostatin and activin A with seemingly no effect on the dissociation rate. This observation is dependent on the heparin/HS chain length where small chain lengths less than degree of polymerization 10 (dp10) did not alter association rates but chain lengths >dp10 decreased association rates. In an attempt to understand the mechanism for this observation, we uncovered that heparin induced dimerization of follistatin. Consistent with our SPR results, we found that dimerization only occurs with heparin molecules >dp10. Small-angle X-ray scattering of the FS288 heparin complex supports that FS288 adopts a dimeric configuration that is similar to the FS288 dimer in the ligand-bound state. These results indicate that heparin mediates dimerization of FS288 in a chain-length-dependent manner that reduces the ligand association rate, but not the dissociation rate or antagonistic activity of FS288.
Topics: Activins; Animals; CHO Cells; Cricetulus; Follistatin; Heparin; Humans; Inhibitory Concentration 50; Ligands; Models, Molecular; Myostatin; Protein Multimerization; Scattering, Small Angle; Static Electricity; Swine; X-Ray Diffraction
PubMed: 33197333
DOI: 10.1177/1535370220966296 -
Biochemical and Biophysical Research... Dec 2023Non-alcoholic fatty liver disease (NAFLD) is currently the most prevalent type of liver disease and a worldwide disease threatening human health. This study aims to...
PURPOSE
Non-alcoholic fatty liver disease (NAFLD) is currently the most prevalent type of liver disease and a worldwide disease threatening human health. This study aims to identify the novel diagnostic biomarkers of NAFLD by comprehensive bioinformatics and machine learning, and to validate our results in hepatocyte and animal models.
METHODS
We used Gene Expression Omnibus (GEO) databases on NAFLD patients for differential gene expression analyses. Intersections were taken with genes from the key modules of WGCNA and differentially expressed genes (DEGs). Machine learning algorithms like LASSO regression analysis, SVM-RFE, and RandomForest were used to screen hub genes. In addition, a nomogram model and calibration curves were built in order to forecast the probability of NAFLD occurrence. Then, the relationship between hub genes and immune cells was verified using Spearman analysis. Finally, we further verified the expression of key genes by constructing a steatosis hepatocyte model and animal model.
RESULTS
Key genes (INHBE and P4HA1) were identified by comprehensive bioinformatics analysis and machine learning. INHBE and P4HA1 were up-regulated and down-regulated in the steatosis hepatocyte model, respectively. Animal experiments also showed that INHBE was up-regulated in the liver of mice fed with high fat diet (HFD).
CONCLUSION
INHBE and P4HA1 are the hub genes of NAFLD. Our findings may contribute to a greater understanding of the occurrence and development of NAFLD and provide potential biomarkers and possible therapeutic targets for future clinical diagnosis and treatment.
Topics: Humans; Animals; Mice; Non-alcoholic Fatty Liver Disease; Hepatocytes; Algorithms; Biomarkers; Inhibin-beta Subunits; Procollagen-Proline Dioxygenase
PubMed: 37922570
DOI: 10.1016/j.bbrc.2023.149180 -
Journal of Autoimmunity Nov 2019The TGF-β superfamily of cytokines plays pivotal roles in the regulation of immune responses protecting against or contributing to diseases, such as, allergy,... (Review)
Review
The TGF-β superfamily of cytokines plays pivotal roles in the regulation of immune responses protecting against or contributing to diseases, such as, allergy, autoimmunity and cancer. Activin-A, a member of the TGF-β superfamily, was initially identified as an inducer of follicle-stimulating hormone secretion. Extensive research over the past decades illuminated fundamental roles for activin-A in essential biologic processes, including embryonic development, stem cell maintenance and differentiation, haematopoiesis, cell proliferation and tissue fibrosis. Activin-A signals through two type I and two type II receptors which, upon ligand binding, activate their kinase activity, phosphorylate the SMAD2 and 3 intracellular signaling mediators that form a complex with SMAD4, translocate to the nucleus and activate or silence gene expression. Most immune cell types, including macrophages, dendritic cells (DCs), T and B lymphocytes and natural killer cells have the capacity to produce and respond to activin-A, although not in a similar manner. In innate immune cells, including macrophages, DCs and neutrophils, activin-A exerts a broad range of pro- or anti-inflammatory functions depending on the cell maturation and activation status and the spatiotemporal context. Activin-A also controls the differentiation and effector functions of Th cell subsets, including Th9 cells, T cells, Tr1 Treg cells and Foxp3 Treg cells. Moreover, activin-A affects B cell responses, enhancing mucosal IgA secretion and inhibiting pathogenic autoantibody production. Interestingly, an array of preclinical and clinical studies has highlighted crucial functions of activin-A in the initiation, propagation and resolution of human diseases, including autoimmune diseases, such as, systemic lupus erythematosus, rheumatoid arthritis and pulmonary alveolar proteinosis, in allergic disorders, including allergic asthma and atopic dermatitis, in cancer and in microbial infections. Here, we provide an overview of the biology of activin-A and its signaling pathways, summarize recent studies pertinent to the role of activin-A in the modulation of inflammation and immunity, and discuss the potential of targeting activin-A as a novel therapeutic approach for the control of inflammatory diseases.
Topics: Active Transport, Cell Nucleus; Activins; Animals; Autoimmune Diseases; Cell Nucleus; Dendritic Cells; Humans; Hypersensitivity; Leukocytes; Neoplasm Proteins; Neoplasms; Smad Proteins
PubMed: 31416681
DOI: 10.1016/j.jaut.2019.102314 -
Biochemical Pharmacology Aug 2023Activins are a subgroup of the TGFβ superfamily of growth and differentiation factors, dimeric in nature and consisting of two inhibin beta subunits linked via a... (Review)
Review
Activins are a subgroup of the TGFβ superfamily of growth and differentiation factors, dimeric in nature and consisting of two inhibin beta subunits linked via a disulfide bridge. Canonical activin signaling occurs through Smad2/3, with negative feedback initiated by Smad6/7 following signal transduction, which binds activin type I receptor preventing phosphorylation of Smad2/3 and activation of downstream signaling. In addition to Smad6/7, other inhibitors of activin signaling have been identified as well, including inhibins (dimers of an inhibin alpha and beta subunit), BAMBI, Cripto, follistatin, and follistatin-like 3 (fstl3). To date, activins A, B, AB, C, and E have been identified and isolated in mammals, with activin A and B having the most characterization of biological activity. Activin A has been implicated as a regulator of several important functions of liver biology, including hepatocyte proliferation and apoptosis, ECM production, and liver regeneration; the role of other subunits of activin in liver physiology are less understood. There is mounting data to suggest a link between dysregulation of activins contributing to various hepatic diseases such as inflammation, fibrosis, and hepatocellular carcinoma, and emerging studies demonstrating the protective and regenerative effects of inhibiting activins in mouse models of liver disease. Due to their importance in liver biology, activins demonstrate utility as a therapeutic target for the treatment of hepatic diseases such as cirrhosis, NASH, NAFLD, and HCC; further research regarding activins may provide diagnostic or therapeutic opportunity for those suffering from various liver diseases.
Topics: Mice; Animals; Follistatin; Carcinoma, Hepatocellular; Liver Neoplasms; Activins; Activin Receptors; Mammals
PubMed: 37364623
DOI: 10.1016/j.bcp.2023.115668