TGF-β signaling in testicular development, spermatogenesis, and infertility
Rajender Singh in Molecular Signaling in Spermatogenesis and Male Infertility, 2019
Activin, a TGF superfamily ligand, is known to regulate a plethora of developmental and reproductive functions in both males and females. Activins were initially identified and isolated for their capacity to induce FSH release (50,51). These are disulfide-linked dimers of inhibin β subunits (βA, βB, βC), such as βAβA (activin A) and βBβB (activin B). Other activin units are also reported including activin C, activin D and activin E. Along with follicle-stimulating hormone (FSH) regulation, it has many other roles to play. Localization studies have identified the testis as the major site for activin production and activin action. In the murine testis, fetal Leydig cells are the source of activin A (34) and activin receptors ACVR2A and ACVR2B localized mainly in gonocytes, interstitial cells and Sertoli cells (13). KO studies have helped in understanding their specific functions, such as inhibin β A (Inhba−/−) mice have lower Sertoli cell number and double the number of gonocytes, inhibin β B (Inhbb−/−) or activin B deficient mice remain fertile (52) and abrogation of activin signaling results in testicular dysgenesis with reduced Sertoli cell number (34). These studies suggest activin A to be a regulator of Sertoli cell proliferation and differentiation, which decides testicular size and sperm production capacity.
Transforming Growth Factor-β: a Multifunctional Growth Regulator
Velibor Krsmanović, James F. Whitfield in Malignant Cell Secretion, 2019
Over the past 3 years, several regulatory molecules, acting in totally different biological contexts, have been shown to be structurally related to TGF-β and constitute with the latter a family of sequence-related proteins. Inhibins and activins are proteins found in ovarian and testicular fluids that control follicle-stimulating hormone (FSH) secretion by the pituitary gland.31-34 The inhibins are heterodimers of two distantly related polypeptide chains α and β, the latter existing in two isoforms βA and βB. These subunits have 134 (α), 116 (βA), and 115 (βB) amino acids per chain and have 7 (α) and 9 (βA and βB) cysteines.32 The β chains A and B show 70% sequence identity and are clearly related to the TGF-β monomer; all three also show very similar positioning of their 9 cysteine residues.32 The activins are also dimers but with only combinations of β chains.33’34 This close structural resemblance between activins and TGF-β helps to explain why the latter possesses activin-like activity.35
Participation of Cytokines and Growth Factors in Biliary Epithelial Proliferation and Mito-Inhibition during Ductular Reactions
Gianfranco Alpini, Domenico Alvaro, Marco Marzioni, Gene LeSage, Nicholas LaRusso in The Pathophysiology of Biliary Epithelia, 2020
In vitro, BEC can produce TGF (beta) mRNA and protein and express the ligand-binding T(beta)R-II.40 Stimulation of cultured BEC with TGF(beta) results in the phosphorylation of SMAD2 and production of p21 protein, which inhibits cell cycle progression.40 In vivo, TGF (beta) 1 is produced primarily by stellate and inflammatory cells, but also by BEC in diseased livers.166,167 TGF(beta)2 is produced primarily by BEC in fibrotic livers.168 Activin A is produced by hepatocytes in normal liver and in stellate cells in diseased livers, particularly at the edge of regenerative nodules. This is the site of ongoing hepatocyte necrosis and ductular reactions.169 After BDL, the BEC stain strongly for TGF(beta)l protein102,167 and its mRNA is upregulated56 at 1 and 4 weeks after ligation, consistent with the down regulation of BEC proliferation at this time.78 In addition, the mannose 6-phosphate/insulin-like growth factor II receptor, which facilitates proteolytic activation of TGF (beta) 1, is also up-regulated in hyperplastic BEC at 1 and 4 weeks after ligation. TGF(beta) 1 may also play a role in morphogenesis as no apical polarization is seen in livers with biliary atresia, compared to the normal embryonic biliary tree.170 TGF(beta)1 can also inhibit progenitor cell proliferation.
Generation of high-yield insulin producing cells from human-induced pluripotent stem cells on polyethersulfone nanofibrous scaffold
Published in Artificial Cells, Nanomedicine, and Biotechnology, 2018
Reyhaneh Nassiri Mansour, Ghasem Barati, Masoud Soleimani, Pegah Ghoraeian, Maryam Nouri Aleagha, Mousa Kehtari, Hossein Mahboudi, Fatemeh Hosseini, Hadi Hassannia, Mohammad Foad Abazari, Seyed Ehsan Enderami
Different growth factors including EGF, bFGF, betacellulin and activin A were used in this study to differentiate hiPSCs into insulin-secreting cells. Different studies showed that EGF and bFGF which play important roles in cell proliferation and survival have a key role in pancreatic lineage neogenesis. These growth factors were secreted from endocrine precursors during islet neogenesis and used as chemo-attractants in islet cell clustering [36–38]. Activin A is a member of the transforming growth factor-beta (TGF-β) superfamily. This protein increases proliferation of beta and ductal-cells during pancreas development, as well as enhancing insulin secretion in response to glucose stimuli [39]. It is observed that Activin A could induce high expression of endocrine genes including Pdx-1, insulin and glucagon in mouse embryonic stem cells [40]. Some studies showed that betacellulin as an EGF family could promote differentiation of the different types of stem cells into insulin-secreting cells [41,42]. One of the factors used in this study to IPC differentiation of hiPSCs was a B27 supplement. B27 is used as a neural supplement and preserve neural cells characteristics in culture [43]. Different studies proved that stem cells can differentiate into IPCs in neural pathways [44,45]. As a result, this supplement could support pancreatic differentiation used in different IPC differentiation studies.
Activin A overexpression promotes rat follicular development through SCF-kit-mediated cell signals
Published in Gynecological Endocrinology, 2020
Yuxia Wang, Luo Shuang, Su Yujie, Ma Xiaohui, Wang Wei, Wang Jidong
The molecular mechanism of follicular development is an unusually complex network system, the details of which are unclear. Activin A is mainly secreted by granulosa cells (paracrine) in the ovaries and has been reported to play a role in promoting cell proliferation and differentiation [1,2]. We predicted that activin A promotes the proliferation of ovarian granulosa cells (GCs). However, the activin A-mediated signaling pathway has not been determined and may involve protein molecules such as Smad2/3, MEK5, ERK5, and Nur77 [3,4]. Some studies showed that the SCF/C-kit signaling system is important in follicular development. Stem cell factor (SCF; also known as kit ligands) is produced by ovarian GCs and functions with the C-kit protein in oocytes. C-kit protein is a tyrosine kinase receptor on the surface of oocytes [5]. SCF and C-kit exert their functions after binding and activation. C-kit is activated by autologous phosphorylation to trigger downstream signal transduction cascade reactions [3,6]. There are specific phosphorylated tyrosine residue sites in C-kit molecules, which can be specifically combined with other signaling proteins [7]. Although SCF and C-kit play an important role in follicular development, their specific mechanism has not been widely examined.
Pharmacotherapeutic options for cancer cachexia: emerging drugs and recent approvals
Published in Expert Opinion on Pharmacotherapy, 2023
Lorena Garcia-Castillo, Giacomo Rubini, Paola Costelli
Anti-Activin Receptor IIB approaches, including those targeting myostatin, have received quite a lot of attention due to the ability of the underlying signal transduction pathway to work as a negative regulator of muscle mass [56]. In this regard, few trials were performed using anti-myostatin tools such as the monoclonal antibody LY2495655 and the AMG745/Mu-S peptibody. While the latter proved effective in improving lean body mass in prostate cancer patients [57], the former failed to confirm such expectations. Indeed, the trial was interrupted due to significant side effects, in the absence of an appreciable clinical benefit [58]. Finally, a phase II clinical trial (ClinicalTrials.gov Identifier: NCT01433263) tested the effectiveness of Bimagrumab, an anti-Activin Receptor in patients affected by advanced lung or pancreatic cancer, showing improved lean body mass. Despite such controversial results, targeting the Activin Receptor II-dependent pathway remains an attractive option that deserves further investigation.
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