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Activin A/Follistatin Axis in Airway Diseases and its Association With Recurrent Exacerbations.

BACKGROUND/AIM: Chronic airway diseases, including chronic obstructive pulmonary disease (COPD), asthma, and asthma COPD overlap (ACO), are characterized by complex inflammatory processes in which Activin A-a key member of the TGF-β superfamily-is implicated. Although its role in the stable state of these diseases has been extensively studied, data regarding its involvement during exacerbations remain limited. Our objective was to investigate the dynamics of Activin A in sputum and serum during acute exacerbations and subsequent convalescence in patients with chronic airway diseases. PATIENTS

Targeting the activin receptor 1C on CD4+ T cells for cancer immunotherapy.

Activins, members of the TGF-beta superfamily, have been isolated and identified in the endocrine system, but have not been substantially investigated in the context of the immune system and endocrine-unrelated cancers. Here, we demonstrated that tumor-bearing mice had elevated systemic activin levels, which correlated directly with tumor burden. Likewise, cancer patients have elevated plasma activin levels compared to healthy controls. We observed that both tumor and immune cells could be sources of activins. Importantly, our in vitro studies suggest that activins promote differentiation of n…

Activin receptors in human cancer: Functions, mechanisms, and potential clinical applications.

Activins are members of the transforming growth factor-β (TGF-β) superfamily and act as key regulators in various physiological processes, such as follicle and embryonic development, as well as in multiple human diseases, including cancer. They have been established to signal through three type I and two type II serine/threonine kinase receptors, which, upon ligand binding, form a final signal-transducing receptor complex that activates downstream signaling and governs gene expression. Recent research highlighted the dysregulation of the expression or activity of activin receptors in multiple …

AAV-Mediated Targeting of the Activin A-ACVR1R206H Signaling in Fibrodysplasia Ossificans Progressiva.

Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare genetic disorder characterized by progressive disabling heterotopic ossification (HO) at extra-skeletal sites. Here, we developed adeno-associated virus (AAV)-based gene therapy that suppresses trauma-induced HO in FOP mice harboring a heterozygous allele of human ACVR1R206H (Acvr1R206H/+) while limiting the expression in non-skeletal organs such as the brain, heart, lung, liver, and kidney. AAV gene therapy carrying the combination of codon-optimized human ACVR1 (ACVR1opt) and artificial miRNAs targeting Activin A and its receptor A

Myostatin/Activin Receptor Ligands in Muscle and the Development Status of Attenuating Drugs.

Muscle wasting disease indications are among the most debilitating and often deadly noncommunicable disease states. As a comorbidity, muscle wasting is associated with different neuromuscular diseases and myopathies, cancer, heart failure, chronic pulmonary and renal diseases, peripheral neuropathies, inflammatory disorders, and, of course, musculoskeletal injuries. Current treatment strategies are relatively ineffective and can at best only limit the rate of muscle degeneration. This includes nutritional supplementation and appetite stimulants as well as immunosuppressants capable of exacerba

Activin A Causes Muscle Atrophy through MEF2C-Dependent Impaired Myogenesis.

Activin A (ActA) is considered to play a major role in cancer-induced cachexia (CC). Indeed, circulating ActA levels are elevated and predict survival in patients with CC. However, the mechanisms by which ActA mediates CC development and in particular skeletal muscle (SM) atrophy in humans are not yet fully understood. In this work, we aimed to investigate the effects of ActA on human SM and in mouse models of CC. We used a model of human muscle cells in culture to explore how ActA acts towards human SM. In this model, recombinant ActA induced myotube atrophy associated with the decline of MyH

Activin Receptor-Ligand Trap for the Treatment of β-thalassemia: A Serendipitous Discovery.

β-thalassemia is a hereditary disorder caused by defective production of β-globin chains of hemoglobin (Hb) that leads to an increased α/β globins ratio with subsequent free α-globins. Alpha globin excess causes oxidative stress, red blood cells membrane damage, premature death of late-stage erythroid precursors, resulting in ineffective erythropoiesis. The transforming growth factor β (TGF-β) superfamily signaling acts on biological processes, such as cell quiescence, apoptosis, proliferation, differentiation, and migration, and plays an essential role in regulating the hematopoiesis. This pa

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… Activins and Activin Receptors Activins are typical proteins members of transforming growth factor β (TGF-β) superfamily and control many cellular processes involved in cell proliferation, death, metabolism, homeostasis, differentiation, immune response, and endocrine function. 4 , 5 Activin A, initially … for intracellular signaling with Activin. …

Inhibin/activin subunits are immunohistochemically expressed in complete and partial hydatidiform moles.

BACKGROUND AND AIM: Inhibins are dimeric glycoproteins, belonging to the transforming growth factor beta (TGF-beta) family, composed of an alpha-subunit (INH-alpha) and one of two possible beta-subunits (betaA or betaB). Additionally two further beta-subunits (betaC and betaE) have been cloned, although their function remains still quite unclear. The detection by immunohistochemistry of inhibin/activin subunits has been proposed as a useful marker of trophoblastic diseases. Interestingly, a complete mole cannot be easily differentiated from a partial mole. Therefore, the aim of this study was

Activin A decreases glucagon and arx gene expression in alpha-cell lines.

Activin A is a potent growth and differentiation factor involved in development, differentiation, and physiological functions of the endocrine pancreas; it increases insulin and pax4 gene expression in beta-cells and can induce transdifferentiation of the exocrine acinar cell line AR42J into insulin-producing cells. We show here that Activin A decreases glucagon gene expression in the alpha-cell lines InR1G9 and alphaTC1 in a dose- and time-dependent manner and that the effect is blocked by Follistatin. This effect is also observed in adult human islets. Glucagon gene expression is inhibited a

Activin A is an endogenous inhibitor of ureteric bud outgrowth from the Wolffian duct.

Development of metanephric kidney begins with ureteric bud outgrowth from the Wolffian duct (WD). GDNF is believed to be a crucial positive signal in the budding process, but the negative regulation of this process remains unclear. Here, we examined the role of activin A, a member of TGF-beta family, in bud formation using an in vitro WD culture system. When cultured with the surrounding mesonephros, WDs formed many ectopic buds in response to GDNF. While the activin signaling pathway is normally active along the non-budding WD (as measured by expression of activin A and phospho-Smad2/3), acti

Activin a in the regulation of corneal neovascularization and vascular endothelial growth factor expression.

Activin A, a dimeric glycoprotein that belongs to the transforming growth factor-beta superfamily, governs cellular differentiation in a wide variety of models and has been implicated in the regulation of angiogenesis. We examined the role of activin A and its downstream signaling pathway in a murine model of inflammatory corneal neovascularization induced by mechanical injury (debridement), and in vitro in corneal epithelial cells. Activin A expression increased steadily from day 2 until day 8 after mechanical debridement in vivo, paralleling vascular endothelial growth factor (VEGF) expressi

Activin betaB expression in rat experimental goiter and human thyroid tumors.

Activins are dimeric proteins of the transforming growth factor beta superfamily, which exhibit multiple functions in gonadal and extragonadal tissues. Expression of activin A, composed of two betaA subunits, has been shown in the thyroid, whereas there has been no study regarding activin B (betaBbetaB) in this gland. In other tissues, such as the gonads, pancreas, and adrenal cortex, expression of both activin betaA and activin betaB has been described. In this study, we detected activin betaB mRNA and protein expression using reverse transcription-polymerase chain reaction (RT-PCR) and immun…

Reduced expression of activin A in focal lymphoid agglomerates within nasal polyps.

It has been previously reported that activin A, a homodimer of the betaA inhibin subunit, is secreted by stromal cells from mouse bone marrow and causes apoptotic death of mouse plasmacytoma tumor cells. Recent in vitro studies have also implicated this cytokine in the suppression of normal B-cell lymphopoiesis. In this study we examined the occurrence of activin A in nasal polyp tissues that present a combination of epithelium, mesenchyme, and vascular endothelium, with frequent massive hemopoietic infiltration. Anti-betaA-chain antibodies strongly stained epithelial mucous glands and some en

Serum immunoreactive activin A levels in normal subjects and patients with various diseases.

We developed and validated a RIA for measuring serum activin A. The least detectable value of this assay was 0.1 micrograms/L, and the antibody used cross-reacted slightly with bovine inhibin (3.2%) and porcine activin AB (10.0%) but not with porcine activin B (< 0.5%). Serum activin A was extracted with acetonitrile and trifluoroacetic acid to get rid of the interaction with possible binding proteins in serum. As a result of this extraction procedure, the dose-response curve of serum extract was parallel to the standard curve and a single immunoreactive (ir-) peak was demonstrated on gel chro

[T-lymphocyte subpopulations in autoimmune and subacute thyroiditis treated with T-activin].

The results of examination of 15 patients with autoimmune and subacute thyroiditis are analyzed. T-cellular immunity parameters have been examined, i.e. total T-lymphocytes, T-suppressors, T-helpers, killers. The study has revealed a reduction of the total T-lymphocyte count and a shifted ratio of the T-lymphocyte subpopulations, these changes being more manifest in autoimmune thyroiditis. T-activin++ therapy resulted in a manifest tendency to normalization of the counts of T-lymphocytes and their subpopulations.

The expression of activins, their type II receptors and follistatin in human Fallopian tube during the menstrual cycle and in pseudo-pregnancy.

BACKGROUND: The Fallopian tube (FT) is the site of fertilization and early embryonic development. We have previously reported the expression of activins, their receptors and follistatin by the FT. Here, our aim was to study the expression of tubal activins, their type II receptors and follistatin during the menstrual cycle and following exposure to hCG in vivo. METHOD: A set of 30 FTs were collected from cycling women (n = 12) at different stages of the cycle (n = 4 in each stage) and pseudo-pregnant women (n = 3) at the time of hysterectomy for benign disease. The pseudo-pregnant women were …

Association of activins, follistatins and inhibins with incident hip fracture in women with postmenopausal osteoporosis: a proof of concept, case-control study.

PURPOSE: The activins-follistatins-inhibins (AFI) hormonal system is considered to regulate muscle and bone mass. We aimed to evaluate AFI in postmenopausal women with an incident hip fracture. METHODS: In this post-hoc analysis of a hospital based case-control study, we evaluated circulating levels of the AFI system in postmenopausal women with a low-energy hip fracture admitted for fixation compared with postmenopausal women with osteoarthritis scheduled for arthroplasty. RESULTS: Circulating levels of follistatin (p = 0.008), FSTL3 (p = 0.013), activin B and AB (both p < 0.001), as well a…

Why does the fallopian tube fail in ectopic pregnancy? The role of activins, inducible nitric oxide synthase, and MUC1 in ectopic implantation.

OBJECTIVE: To investigate the role of activin-βA subunit, activin type II receptors, inducible nitric oxide synthase (iNOS), and MUC1 in the pathogenesis of ectopic pregnancy (EP) and their involvement in the determination of the implantation site. DESIGN: Observational study. SETTING: Academic unit of reproductive and developmental medicine. PATIENT(S): Four women at the luteal phase, three pseudopregnant women at the time of hysterectomy for benign disease, and 10 archived cases of EP. We collected 14 Fallopian tubes were collected from four women at the luteal phase and three pseudopregn

Impact of Excess Activin A on the Lipids, Metabolites, and Steroids of Adult Mouse Reproductive Organs.

Bioactivity of the hormone and growth factor activin A is central to fertility and health. Dysregulated circulating activin levels occur with medication usage and multiple pathological conditions. The inhibin-alpha knockout mouse (InhaKO) models chronic activin elevation and unopposed activin A bioactivity. In InhaKO fetal testes, lipid droplet, steroid profiles, and seminiferous cords are abnormal; adults develop gonadal and adrenal tumors due to chronic activin A excess exposure. Here we address how this exposure affects lipid, metabolite, and steroid composition in whole testes, ovaries, an

Roles of Activin A and Gpnmb in Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD).

Metabolic dysfunction-associated steatotic liver disease (MASLD, formerly known as nonalcoholic fatty liver disease [NAFLD]) and metabolic dysfunction-associated steatohepatitis (MASH, formerly known as nonalcoholic steatohepatitis [NASH]) are leading chronic liver diseases, driving cirrhosis, hepatocellular carcinoma, and mortality. MASLD/MASH is associated with increased senescence proteins, including Activin A, and senolytics have been proposed as a therapeutic approach. To test the role of Activin A, we induced hepatic expression of Activin A in a murine MASLD/MASH model. Surprisingly, ove