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Diabetes, Obesity & Metabolism Sep 2014The 20 different amino acids, in blood as well as in the brain, are strictly maintained at the same levels throughout the day, regardless of food intake. Gastric vagal... (Review)
Review
The 20 different amino acids, in blood as well as in the brain, are strictly maintained at the same levels throughout the day, regardless of food intake. Gastric vagal afferents only respond to free glutamate and sugars, providing recognition of food intake and initiating digestion. Metabolic control of amino acid homeostasis and diet-induced thermogenesis is triggered by this glutamate signalling in the stomach through the gut-brain axis. Rats chronically fed high-sugar and high-fat diets do not develop obesity when a 1% (w/v) monosodium glutamate (MSG) solution is available in a choice paradigm. Deficiency of the essential amino acid lysine (Lys) induced a plasticity in rats in response to Lys. This result shows how the body is able to identify deficient nutrients to maintain homeostasis. This plastic effect is induced by activin A activity in the brain, particularly in certain neurons in the lateral hypothalamic area (LHA) which is the centre for amino acid homeostasis and appetite. These neurons respond to glutamate signalling in the oral cavity by which umami taste is perceived. They play a quantitative role in regulating ingestion of deficient nutrients, thereby leading to a healthier life. After recovery from malnutrition, rats prefer MSG solutions, which serve as biomarkers for protein nutrition.
Topics: Activins; Amino Acids; Animals; Appetite Regulation; Brain; Feedback, Physiological; Humans; Hypothalamic Area, Lateral; Inhibin-beta Subunits; Models, Neurological; Nerve Tissue Proteins; Neuronal Plasticity; Neurons; Organ Specificity
PubMed: 25200295
DOI: 10.1111/dom.12336 -
Expert Opinion on Investigational Drugs 2015In cancer patients, anemia is frequently observed, particularly as a consequence to chemotherapy (chemotherapy-induced anemia, CIA). CIA is treated with Red Blood Cell... (Review)
Review
INTRODUCTION
In cancer patients, anemia is frequently observed, particularly as a consequence to chemotherapy (chemotherapy-induced anemia, CIA). CIA is treated with Red Blood Cell transfusions and erythropoiesis-stimulating agents (ESAs). However, the use of ESAs in anemic cancer patients is associated with reduced survival time and time to progression. Consequently, new therapeutic options are needed.
AREAS COVERED
In this article, the authors discuss new erythroid-enhancing agents (EEAs) that act differently to erythropoietin. Specifically, the article summarizes the early clinical development of activin antagonists (Sotatercep [ACE-011] and ACE-536) and hepcidin antagonists [NOX-H94]).
EXPERT OPINION
Both Activin RIIA trap agents and hepcidin inhibitors are promising new EEAs, but their safety profile, and their impact on treating CIA, needs to be carefully assessed in controlled clinical trials over longer periods of time. It is also important to carefully evaluate CIA patients to properly assess the physiopathological mechanisms responsible for the development of their anemic condition and provide patients with the most appropriate treatment plan.
Topics: Activins; Anemia; Animals; Antineoplastic Agents; Disease Progression; Drug Design; Drugs, Investigational; Hematinics; Hepcidins; Humans; Neoplasms
PubMed: 26359222
DOI: 10.1517/13543784.2015.1085505 -
Trends in Molecular Medicine Dec 2020Wound repair is a highly regulated process that requires the interaction of various cell types. It has been shown that cancers use the mechanisms of wound healing to... (Review)
Review
Wound repair is a highly regulated process that requires the interaction of various cell types. It has been shown that cancers use the mechanisms of wound healing to promote their own growth. Therefore, it is of importance to identify common regulators of wound repair and tumor formation and to unravel their functions and mechanisms of action. An exciting example is activin, which acts on multiple cell types in wounds and tumors, thereby promoting healing, but also scar formation and tumorigenesis. Here, we summarize current knowledge on the role of activin in these processes and highlight the therapeutic potential of activin or activin antagonists for the treatment of impaired healing or excessive scarring and cancer, respectively.
Topics: Activins; Animals; Biomarkers; Cicatrix; Disease Susceptibility; Fibroblasts; Humans; Neoplasms; Wound Healing
PubMed: 32878730
DOI: 10.1016/j.molmed.2020.07.009 -
Women & Health Sep 2021The aim of the present study was to investigate serum and urine levels of activin A in different moments of gestation, in primigravidae and in multigravidae, to...
The aim of the present study was to investigate serum and urine levels of activin A in different moments of gestation, in primigravidae and in multigravidae, to understand whether these variables (biological sample and first gestation) affect activin A as a biomarker in pregnancy. We prospectively included 43 pairs of serum and urine samples from 25 women examined at different gestational ages (range 45 to 268 days). In the group of primigravidae (n = 16 samples from 9 participants), there was no significant change in serum activin A levels across gestation. Conversely, the group of multigravidae (n = 27 samples from 16 women) had higher serum activin A levels in the third trimester (2676 ± 840 pg/ml) compared to the first (583 ± 408 pg/ml) and second (1040 ± 384) trimesters ( = .025). Urine activin A concentrations did not differ between the two groups and did not change according to the gestation phase. There was no correlation between serum and urinary levels of activin A (r = 0.149, = .359). These data suggest that activin A secretion may vary less during the first pregnancy, while urine activin A is unlikely to be a surrogate for the systemic levels of this hormone in pregnant women.
Topics: Activins; Cross-Sectional Studies; Female; Humans; Pregnancy; Pregnancy Trimester, Third; Prospective Studies
PubMed: 34376125
DOI: 10.1080/03630242.2021.1965693 -
Activin A Modulates Betaglycan Shedding via the ALK4-SMAD3-Dependent Pathway in Endometriotic Cells.Biomolecules Nov 2022The TGF-β superfamily members, activins and inhibins, are mainly involved in cell proliferation, cell survival, invasion, immune surveillance, and lesion growth in...
The TGF-β superfamily members, activins and inhibins, are mainly involved in cell proliferation, cell survival, invasion, immune surveillance, and lesion growth in endometriosis. Herein, we investigated the modulation of the TGF-β type III receptor (betaglycan or BG) by activin A and inhibin A in endometriosis in vitro. Often, BG undergoes ectodomain shedding releasing soluble BG (sBG) which frequently antagonizes TGF-β signaling. The effects of activin A on BG shedding and signaling pathways involved were evaluated with the inhibitors LY364947 and SIS3, siRNA knockdown in human endometrial cells (12Z, THESC, Ishikawa, and primary stromal cells) and were quantified with BG ELISAs. The effects of activin A and inhibin A on the secretion of MMP2 and MMP3 were analyzed using ELISAs. The effects of activin A on the BG expression were analyzed using RT-qPCR and western blot. The CCK-8 and BrdU assays were used to evaluate the effects of the recombinant BG on cell viability and proliferation. Activin A stimulation resulted in a significant time- and dose-dependent reduction in BG shedding, which was found to be activin A/ALK-4/SMAD3- but not SMAD2-dependent. Activin A increased the BG mRNA expression but had no effect on the protein expression. Likewise, inhibin A was found to block BG shedding. Activin A, but not inhibin A, significantly enhanced the secretion of MMP2 and MMP3. The recombinant BG had no effect on the viability and proliferation of endometriotic cells. Together, these observations support a novel role for activin A with BG in modulating the TGF-β superfamily ligands in endometrial cells in vitro.
Topics: Female; Humans; Activins; Endometriosis; Matrix Metalloproteinase 2; Matrix Metalloproteinase 3; Smad3 Protein; Transforming Growth Factor beta; Receptors, Transforming Growth Factor beta; Activin Receptors, Type I
PubMed: 36551177
DOI: 10.3390/biom12121749 -
Molecular Endocrinology (Baltimore, Md.) Jul 2015The activins were discovered and named based on their abilities to stimulate FSH secretion and FSHβ (Fshb) subunit expression by pituitary gonadotrope cells. According... (Review)
Review
The activins were discovered and named based on their abilities to stimulate FSH secretion and FSHβ (Fshb) subunit expression by pituitary gonadotrope cells. According to subsequent in vitro observations, activins also stimulate the transcription of the GnRH receptor (Gnrhr) and the activin antagonist, follistatin (Fst). Thus, not only do activins stimulate FSH directly, they have the potential to regulate both FSH and LH indirectly by modulating gonadotrope sensitivity to hypothalamic GnRH. Moreover, activins may negatively regulate their own actions by stimulating the production of one of their principal antagonists. Here, we describe our current understanding of the mechanisms through which activins regulate Fshb, Gnrhr, and Fst transcription in vitro. The activin signaling molecules SMAD3 and SMAD4 appear to partner with the winged-helix/forkhead transcription factor, forkhead box L2 (FOXL2), to regulate expression of all 3 genes. However, in vivo data paint a different picture. Although conditional deletion of Foxl2 and/or Smad4 in murine gonadotropes produces impairments in FSH synthesis and secretion as well as in pituitary Fst expression, Gnrhr mRNA levels are either unperturbed or increased in these animals. Surprisingly, gonadotrope-specific deletion of Smad3 alone or with Smad2 does not impair FSH production or fertility; however, mice harboring these mutations may express a DNA binding-deficient, but otherwise functional, SMAD3 protein. Collectively, the available data firmly establish roles for FOXL2 and SMAD4 in Fshb and Fst expression in gonadotrope cells, whereas SMAD3's role requires further investigation. Gnrhr expression, in contrast, appears to be FOXL2, SMAD4, and, perhaps, activin independent in vivo.
Topics: Activins; Animals; Forkhead Transcription Factors; Gene Expression Regulation; Gonadotrophs; Humans; Signal Transduction; Smad Proteins
PubMed: 25942106
DOI: 10.1210/me.2015-1004 -
Molecular Therapy : the Journal of the... Mar 2015Soluble activin type II receptors (ActRIIA/ActRIIB), via binding to diverse TGF-β proteins, can increase muscle and bone mass, correct anemia or protect against...
Soluble activin type II receptors (ActRIIA/ActRIIB), via binding to diverse TGF-β proteins, can increase muscle and bone mass, correct anemia or protect against diet-induced obesity. While exciting, these multiple actions of soluble ActRIIA/IIB limit their therapeutic potential and highlight the need for new reagents that target specific ActRIIA/IIB ligands. Here, we modified the activin A and activin B prodomains, regions required for mature growth factor synthesis, to generate specific activin antagonists. Initially, the prodomains were fused to the Fc region of mouse IgG2A antibody and, subsequently, "fastener" residues (Lys(45), Tyr(96), His(97), and Ala(98); activin A numbering) that confer latency to other TGF-β proteins were incorporated. For the activin A prodomain, these modifications generated a reagent that potently (IC(50) 5 nmol/l) and specifically inhibited activin A signaling in vitro, and activin A-induced muscle wasting in vivo. Interestingly, the modified activin B prodomain inhibited both activin A and B signaling in vitro (IC(50) ~2 nmol/l) and in vivo, suggesting it could serve as a general activin antagonist. Importantly, unlike soluble ActRIIA/IIB, the modified prodomains did not inhibit myostatin or GDF-11 activity. To underscore the therapeutic utility of specifically antagonising activin signaling, we demonstrate that the modified activin prodomains promote significant increases in muscle mass.
Topics: Activins; Animals; Bone Morphogenetic Proteins; Dependovirus; Gene Expression Regulation; Genetic Engineering; Genetic Vectors; Growth Differentiation Factors; HEK293 Cells; Humans; Immunoglobulin Fc Fragments; Immunoglobulin G; Male; Mice; Mice, Inbred C57BL; Muscle, Skeletal; Myostatin; Plasmids; Protein Structure, Tertiary; Recombinant Fusion Proteins; Signal Transduction; Transfection; Transforming Growth Factor beta
PubMed: 25399825
DOI: 10.1038/mt.2014.221 -
Fertility and Sterility Jun 2021
Topics: Activins; Humans; Leiomyoma; Phenotype
PubMed: 33863554
DOI: 10.1016/j.fertnstert.2021.03.021 -
International Journal of Cancer Aug 2023Although KMT2D, also known as MLL2, is known to play an essential role in development, differentiation, and tumor suppression, its role in pancreatic cancer development...
Although KMT2D, also known as MLL2, is known to play an essential role in development, differentiation, and tumor suppression, its role in pancreatic cancer development is not well understood. Here, we discovered a novel signaling axis mediated by KMT2D, which links TGF-β to the activin A pathway. We found that TGF-β upregulates a microRNA, miR-147b, which in turn leads to post-transcriptional silencing of KMT2D. Loss of KMT2D induces the expression and secretion of activin A, which activates a noncanonical p38 MAPK-mediated pathway to modulate cancer cell plasticity, promote a mesenchymal phenotype, and enhance tumor invasion and metastasis in mice. We observed a decreased KMT2D expression in human primary and metastatic pancreatic cancer. Furthermore, inhibition or knockdown of activin A reversed the protumoral role of KMT2D loss. These findings support a tumor-suppressive role of KMT2D in pancreatic cancer and identify miR-147b and activin A as novel therapeutic targets.
Topics: Humans; Animals; Mice; Cell Plasticity; Cell Line, Tumor; MicroRNAs; Pancreatic Neoplasms; Transforming Growth Factor beta; Activins
PubMed: 37140208
DOI: 10.1002/ijc.34528 -
ELife Jun 2022Activin ligands are formed from two disulfide-linked inhibin β (Inhβ) subunit chains. They exist as homodimeric proteins, as in the case of activin A (ActA;...
Activin ligands are formed from two disulfide-linked inhibin β (Inhβ) subunit chains. They exist as homodimeric proteins, as in the case of activin A (ActA; InhβA/InhβA) or activin C (ActC; InhβC/InhβC), or as heterodimers, as with activin AC (ActAC; InhβA:InhβC). While the biological functions of ActA and activin B (ActB) have been well characterized, little is known about the biological functions of ActC or ActAC. One thought is that the InhβC chain functions to interfere with ActA production by forming less active ActAC heterodimers. Here, we assessed and characterized the signaling capacity of ligands containing the InhβC chain. ActC and ActAC activated SMAD2/3-dependent signaling via the type I receptor, activin receptor-like kinase 7 (ALK7). Relative to ActA and ActB, ActC exhibited lower affinity for the cognate activin type II receptors and was resistant to neutralization by the extracellular antagonist, follistatin. In mature murine adipocytes, which exhibit high ALK7 expression, ActC elicited a SMAD2/3 response similar to ActB, which can also signal via ALK7. Collectively, these results establish that ActC and ActAC are active ligands that exhibit a distinct signaling receptor and antagonist profile compared to other activins.
Topics: Activin Receptors; Activin Receptors, Type I; Activins; Animals; Ligands; Mice; Signal Transduction
PubMed: 35736809
DOI: 10.7554/eLife.78197